Benzylidenethiazolidine derivatives and their use for the inhibition lipid peroxides

ABSTRACT

Benzylidenethiazolidine compounds of formula (I): ##STR1## [in which R 1 , R 2  and R 5  are each hydrogen or alkyl; R 3  and R 4  are each hydrogen, alkyl, formyl, alkylcarbonyl, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, hydroxy, alkylcarbonyloxy, formyloxy, arylcarbonyloxy, optionally substituted alkoxy or halogen; W is methylene, carbonyl or a group of formula &gt;C═N--OV, wherein V is hydrogen, alkylcarbonyl, arylcarbonyl or optionally substituted alkyl; and n is an integer of from 1 to 3] and salts thereof have the ability to inhibit the formation of lipid peroxide in the mammalian body, and can therefore be used for the treatment of arteriosclerosis and other diseases and disorders arising from an imbalance in the lipid peroxide level. They can also be used for the preparation of the corresponding benzylthiazolidine compounds, which have a generally greater hypoglycemic activity. Processes for the preparation of these compounds of formula (I) are also provided.

This application is a continuation, of application Ser. No. 07/687,431,filed Apr. 18, 1991 (abandoned).

BACKGROUND TO THE INVENTION

The present invention relates to a series of novelbenzylidenethiazolidine derivatives which have the ability to inhibitthe formation of lipid peroxide in the mammalian body, to the use ofthese compounds for the treatment of arteriosclerosis and other diseasesand disorders arising from an imbalance in the lipid peroxide level, toprocesses for the preparation of these compounds and to processes usingthese compounds for the preparation of other active compounds.

Certain thiazolidinone derivatives having the ability to lower bloodlipid and blood glucose levels are disclosed in U.S. Pat. No. 4,572,912and in U.S. patent application Ser. No. 833,867 filed the 25th day ofFeb. 1986. Other thiazolidinone derivatives having a similar type ofactivity are disclosed in European Pat. No. 8203; but such compounds arestructurally less similar to those of the present invention. However,the closest prior art of which we are presently aware is U.S. Pat. No.4,873,255, which discloses a series of compounds which differ from thoseof the present invention in that they are benzylthiazolidinederivatives, rather than the benzylidenethiazolidine derivatives of thepresent invention.

We have now discovered a series of novel benzylidenethiazolidinederivatives which not only have the ability to inhibit the activity oflipid peroxide in the mammalian metabolism, but which also are ofconsiderable value in preparing cheaply, effectively and in relativelyhigh yields the compounds of the aforementioned U.S. Pat. No. 4,873,255,which are at present thought to be of greater value for theirtherapeutic activity.

BRIEF SUMMARY OF INVENTION

Thus, the compounds of the present invention may be represented by theformula (I): ##STR2## in which R¹, R² and R⁵ are independently selectedfrom the group consisting of hydrogen atoms and alkyl groups having from1 to 10 carbon atoms;

R³ and R⁴ are independently selected from the group consisting of:hydrogen atoms; alkyl groups having from 1 to 10 carbon atoms; formylgroups; alkylcarbonyl groups having from 2 to 11 carbon atoms;arylcarbonyl groups in which the aryl part has from 6 to 10 ring carbonatoms and is unsubstituted or is substituted by at least one substituentselected from the group consisting of substituents (a), defined below;carboxy groups; alkoxycarbonyl groups having from 2 to 7 carbon atoms;aryloxycarbonyl groups in which the aryl part has from 6 to 10 ringcarbon atoms and is unsubstituted or is substituted by at least onesubstituent selected from the group consisting of substituents (a),defined below; hydroxy groups; alkylcarbonyloxy groups having from 2 to11 carbon atoms; formyloxy groups; arylcarbonyloxy groups in which thearyl part has from 6 to 10 ring carbon atoms and is unsubstituted or issubstituted by at least one substituent selected from the groupconsisting of substituents (a), defined below; alkoxy groups having from1 to 5 carbon atoms; substituted alkoxy groups having from 1 to 5 carbonatoms and substituted by at least one substituent selected from thegroup consisting of substituents (b), defined below; and halogen atoms;

W represents a methylene group (>CH₂), a carbonyl group (>C═O) or agroup of formula >C═N--OV

wherein V represents: a hydrogen atom; an alkylcarbonyl group havingfrom 2 to 6 carbon atoms; an arylcarbonyl group in which the aryl parthas from 6 to 10 ring carbon atoms and is unsubstituted or issubstituted by at least one substituent selected from the groupconsisting of substituents (a), defined below; an alkyl group havingfrom 1 to 5 carbon atoms; a substituted alkyl group having from 1 to 5carbon atoms and substituted by at least one substituent selected fromthe group consisting of substituents (d), defined below; and

n is an integer of from 1 to 3;

substituents (a):

alkyl groups having from 1 to 5 carbon atoms; alkoxy groups having from1 to 5 carbon atoms; and halogen atoms;

substituents (b):

aryl groups which have from 6 to 10 ring carbon atoms and which areunsubstituted or which have at least one substituent selected from thegroup consisting of substituents (a), defined above; carboxy groups;alkoxycarbonyl groups having from 2 to 6 carbon atoms; and groups offormula --CONR⁶ R⁷, where

R⁶ and R⁷ are independently selected from the group consisting of:hydrogen atoms; alkyl groups having from 1 to 5 carbon atoms; and arylgroups which have from 6 to 10 ring carbon atoms and which areunsubstituted or which have at least one substituent selected from thegroup consisting of substituents (a), defined above; or R⁶ and R⁷,together with the nitrogen atom to which they are attached, form aheterocyclic group which has from 3 to 7 ring atoms, of which 1 is saidnitrogen atom and 0 or 1 is an additional hetero-atom selected from thegroup consisting of nitrogen, oxygen and sulfur hetero-atoms, saidheterocyclic group being unsubstituted or being substituted by at leastone substituent selected from the group consisting of substituents (c),defined below;

substituents (c):

alkyl groups having from 1 to 5 carbon atoms; and aryl groups which havefrom 6 to 10 ring carbon atoms and which are unsubstituted or which haveat least one substituent selected from the group consisting ofsubstituents (a), defined above;

substituents (d):

carboxy groups and alkoxycarbonyl groups having from 2 to 6 carbonatoms;

and pharmaceutically acceptable salts thereof.

The invention still further provides a pharmaceutical composition forthe treatment or prophylaxis of diseases and disorders arising from animbalance in the lipid peroxide level, said composition comprising aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof in admixture with a pharmaceutically acceptablecarrier or diluent.

The invention still further provides a method of reducing lipid peroxidelevels in an animal, especially a mammal, e.g. a human being, byadministering to said animal an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

The invention still further provides processes for preparing thecompounds of the invention and for using the compounds of the inventionto prepare benzylthiazolidine derivatives, as described in greaterdetail hereafter.

DETAILED DESCRIPTION OF INVENTION

In the compounds of the present invention where R¹, R², R³, R⁴ or R⁵represents an alkyl group having from 1 to 10 carbon atoms, this may bea straight or branched chain alkyl group, and examples include themethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl,neohexyl, 1-methylpentyl, 3-methylpentyl, 1,3-dimethylbutyl,2-ethylbutyl, heptyl, 1-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl,octyl, 1-methylheptyl, 2-ethylhexyl, 5,5-dimethylhexyl,1,1,3,3-tetramethylbutyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyland 7,7-dimethyloctyl groups. Of these, we prefer that R¹, R², R³, R⁴and R⁵ should represent a straight or branched chain alkyl group havingfrom 1 to 4 carbon atoms. More preferably, where R¹, R², R³ or R⁵represents an alkyl group, it is a methyl, ethyl, propyl, isopropyl,butyl or isobutyl group, and most preferably a methyl group. Morepreferably, where R⁴ represents an alkyl group, it is a methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl group, and mostpreferably a methyl or t-butyl group, particularly a methyl group.

Where R³ and/or R⁴ represents an alkylcarbonyl group, this may be astraight or branched chain alkylcarbonyl group having from 2 to 11carbon atoms. Examples of such alkylcarbonyl groups include the acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,2-methylpentanoyl, heptanoyl, isoheptanoyl, octanoyl, isooctanoyl,nonanoyl, 2-methyloctanoyl, isononanoyl, decanoyl and undecanoyl groups.Preferably, where R³ and/or R⁴ represents an alkylcarbonyl group, thisis a straight or branched chain alkylcarbonyl group having from 2 to 7carbon atoms, more preferably a straight or branched chain alkylcarbonylgroup having from 2 to 5 carbon atoms, and most preferably an acetylgroup.

Where R³ and/or R⁴ represents an arylcarbonyl group, whose aryl grouphas from 6 to 10 carbon atoms and may optionally have one or moresubstituents, it has, excluding any substituents, a total of from 7 to11 carbon atoms. Examples of such groups include the benzoyl,1-naphthoyl and 2-naphthoyl groups, which may be unsubstituted orsubstituted. Where the aryl moiety is substituted, we prefer that itshould have from 1 to 5 substituents on the aromatic ring. Thesesubstituents are selected from the group consisting of substituents (a),and examples of such substituents include:

(1) straight and branched chain alkyl groups having from 1 to 5 carbonatoms, such as the methyl, ethyl propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl and1-ethylpropyl groups;

(2) straight and branched chain alkoxy groups having from 1 to 5 carbonatoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, t-butoxy, pentyloxy and isopentyloxy groups; and

(3) halogen atoms, such as the chlorine, fluorine and bromine atoms.

Examples of such groups which may be represented by R³ and/or R⁴include: (a) the benzoyl, 1-naphthoyl and 2-naphthoyl groups; (b) the4-methylbenzoyl, 2-propylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl,4-methyl-1-naphthoyl and 4-propyl-2-naphthoyl groups; (c) the2-methoxybenzoyl, 4-ethoxybenzoyl, 4-butoxybenzoyl,4-isopentyloxybenzoyl and 4-methoxy-1-naphthoyl groups; and (d) the3-chlorobenzoyl, 4-fluorobenzoyl, 4-bromobenzoyl and4-chloro-2-naphthoyl groups. Where R³ and/or R⁴ represents anarylcarbonyl group, this is preferably an arylcarbonyl group having from7 to 11 carbon atoms whose aryl moiety has no substituents, and is mostpreferably a benzoyl group.

Where R³ and/or R⁴ represents an alkoxycarbonyl group, the alkoxy partmay be a straight or branched chain group having from 1 to 6 carbonatoms, i.e. the alkoxycarbonyl group has from 2 to 7 carbon atoms.Examples of such alkoxycarbonyl groups include the methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl,2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl,neohexyloxycarbonyl, 1-methylpentyloxycarbonyl,3-methylpentyloxycarbonyl, 1,3-dimethylbutoxycarbonyl and2-ethylbutoxycarbonyl groups. Preferably R³ represents a straight orbranched chain alkoxycarbonyl group having from 2 to 5 carbon atoms andmost preferably a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonylgroup. Preferably R⁴ represents a straight or branched chainalkoxycarbonyl group having from 2 to 5 carbon atoms.

Where R³ and/or R⁴ represents an aryloxycarbonyl group, whose aryl parthas from 6 to 10 carbon atoms and may optionally have one or moresubstituents, it has, excluding any substituents, a total of from 7 to11 carbon atoms. Examples of such groups include the phenoxycarbonyl,1-naphthyloxycarbonyl and 2-naphthyloxycarbonyl groups, which may beunsubstituted or substituted. Where the aryl moiety is substituted, weprefer that it should have from 1 to 5 substituents on the aromaticring. These substituents are selected from the group consisting ofsubstituents (a), and examples of such substituents are as given above.Examples of such groups which may be represented by R³ and/or R⁴include: (a) the phenoxycarbonyl, 1-naphthyloxycarbonyl and2-naphthyloxycarbonyl groups; (b) the 4-methylphenoxycarbonyl,2-propylphenoxycarbonyl, 3-butylphenoxycarbonyl,4-pentylphenoxycarbonyl, 4-methyl-1-naphthyloxycarbonyl and4-propyl-2-naphthyloxycarbonyl groups; (c) the 2-methoxyphenoxycarbonyl,4-ethoxyphenoxycarbonyl, 4-butoxyphenoxycarbonyl,4-isopentyloxyphenoxycarbonyl and 4-methoxy-1-naphthyloxycarbonylgroups; and (d) the 3-chlorophenoxycarbonyl, 4-fluorophenoxycarbonyl,4-bromophenoxycarbonyl and 4-chloro-2-naphthyloxycarbonyl groups. WhereR³ and/or R⁴ represents an aryloxycarbonyl group, this is preferably anaryloxycarbonyl group having from 7 to 11 carbon atoms whose aryl moietyhas no substituents, and is most preferably a phenoxycarbonyl group.

Where R³ and/or R⁴ represents an alkylcarbonyloxy group, the alkyl partmay be a straight or branched chain group having from 1 to 10 carbonatoms, i.e. the alkylcarbonyl group has from 2 to 11 carbon atoms.Examples of such alkylcarbonyloxy groups include the acetoxy,propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy,pivaloyloxy, hexanoyloxy, 2-methylpentanoyloxy, heptanoyloxy,isoheptanoyloxy, octanoyloxy, isooctanoyloxy, nonanoyloxy,2-methyloctanoyloxy, isononanoyloxy, decanoyloxy and undecanoyloxygroups. Where R³ and/or R⁴ represents an alkylcarbonyloxy group, this ispreferably a straight or branched chain alkylcarbonyloxy group havingfrom 2 to 7 carbon atoms, more preferably a straight or branched chainalkylcarbonyloxy group having from 2 to 5 carbon atoms, and mostpreferably an acetoxy group.

Where R³ and/or R⁴ represents an arylcarbonyloxy group, whose aryl grouphas from 6 to 10 carbon atoms and may optionally have one or moresubstituents, it has, excluding any substituents, a total of from 7 to11 carbon atoms. Examples of such groups include the benzoyloxy,1-naphthoyloxy and 2-naphthoyloxy groups, which may be unsubstituted orsubstituted. Where the aryl moiety is substituted, we prefer that itshould have from 1 to 5 substituents on the aromatic ring. Thesesubstituents are selected from the group consisting of substituents (a),and examples of such substituents are as illustrated above. Examples ofsuch groups which may be represented by R³ and/or R⁴ include: (a) thebenzoyloxy, 1-naphthoyloxy and 2-naphthoyloxy groups; (b) the4-methylbenzoyloxy, 2-propylbenzoyloxy, 3-butylbenzoyloxy,4-pentylbenzoyloxy, 4-methyl-1-naphthoyloxy and 4-propyl-2-naphthoyloxygroups; (c) the 2-methoxybenzoyloxy, 4-ethoxybenzoyloxy,4-butoxybenzoyloxy, 4-isopentyloxybenzoyloxy and4-methoxy-1-naphthoyloxy groups; and (d) the 3-chlorobenzoyloxy,4-fluorobenzoyloxy, 4-bromobenzoyloxy and 4-chloro-2-naphthoyloxygroups. Where R³ and/or R⁴ represents an arylcarbonyloxy group, this ispreferably an arylcarbonyloxy group having from 7 to 11 carbon atomswhose aryl moiety has no substituents, and most preferably a benzoyloxygroup.

Where R³ and/or R⁴ represents an alkoxy group, this may be a straight orbranched chain alkoxy group having from 1 to 5 carbon atoms and it maybe unsubstituted or it may have one or more substituents selected fromthe group consisting of substituents (b), defined above and exemplifiedbelow. Examples of such groups include the methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy andisopentyloxy groups, which may be unsubstituted or may be substituted byone or more of substituents (b). Although the number of substituents is,in principle, limited only by the number of substitutable positions andpossibly by steric constraints, in practice, we normally prefer from 1to 3 substituents. Examples of such substituents include:

(1) aryl groups which may be unsubstituted or may have one or moresubstituents; these may be as defined above in relation to the arylgroups which may be represented by R³ and R4; examples include thephenyl, 1-naphthyl and 2-naphthyl groups, which may be unsubstituted ormay be substituted, preferably with from 1 to 5 substituents, as definedabove;

(2) carboxy groups;

(3) alkoxycarbonyl groups having from 2 to 6 carbon atoms, which may bestraight or branched chain groups, for example the methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl,2-methylbutoxycarbonyl and 1-ethylpropoxycarbonyl groups;

(4) groups of formula --CONR⁶ R⁷ (wherein R⁶ and R⁷ are the same ordifferent and each represents:

a hydrogen atom,

a straight or branched chain alkyl group having from 1 to 5 carbonatoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl and1-ethylpropyl groups,

an aryl group which may be unsubstituted or may be substituted by one ormore of substituents (a), defined and exemplified above, and which hasfrom 6 to 10 carbon atoms, such as the phenyl, 1-naphthyl and 2-naphthylgroups and substituted analogs thereof, as exemplified above,

R⁶ and R⁷, together with the nitrogen atom to which they are attached,may form a heterocyclic ring, as defined and exemplified below.

The heterocyclic group which may be formed by the --NR⁶ R⁷ part of thegroup of formula --CONR⁶ R⁷ has from 3 to 7 ring atoms and is preferablya saturated group, which may optionally contain an additional oxygen,sulfur or nitrogen atom in the ring. The group may be unsubstituted orit may be substituted by at least one of substituents (c), defined aboveand exemplified below, in particular, where the heterocyclic groupcontains an additional nitrogen atom, the nitrogen atom may optionallybe substituted; examples of these substituents include:

(i) straight or branched chain alkyl groups having from 1 to 5 carbonatoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl and1-ethylpropyl groups, and

(ii) aryl groups which may optionally be substituted by one or more ofsubstituents (a) and which, excluding any substituents, have from 6 to10 carbon atoms, such as the phenyl, 1-naphthyl and 2-naphthyl group,and such groups having one or more substituents, as defined andexemplified above in relation to R³ and R⁴.

Examples of these heterocyclic groups include the 1-pyrrolidinyl,piperidino, morpholino, piperazinyl, N-methylpiperazinyl,N-phenylpiperazinyl, N-(4-methylphenyl)piperazinyl,N-(3-methoxyphenyl)piperazinyl and N-(2-chlorophenyl) piperazinylgroups.

Examples of the substituted and unsubstituted alkoxy groups which may berepresented by R³ or R⁴ include: (a) the methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy andisopentyloxy groups, (b) the benzyloxy, phenethyloxy, 3-phenylpropoxy,α-naphthylmethoxy and β-naphthylmethoxy groups, (c) the4-methylbenzyloxy, 4-butylbenzyloxy, 4-ethylphenethyloxy and5-methyl-α-naphthylmethoxy groups, (d) the 4-methoxybenzyloxy,4-ethoxybenzyloxy, 4-butoxyphenethyloxy and 5-methoxyα-naphthylmethoxygroups, (e) the 4-chlorobenzyloxy, 4-bromobenzyloxy,4-fluorophenethyloxy and 5-chloro-α-napthylmethoxy groups, (f) thecarboxymethoxy, 2-carboxyethoxy, 3-carboxypropoxy, 3-carboxybutoxy,3-carboxy-1-methylpropoxy and 1-carboxy-1-methylethoxy groups, (g) themethoxycarbonylmethoxy, 3-methoxycarbonylpropoxy,2-propoxycarbonylethoxy, 3-pentyloxycarbonylpropoxy,4-butoxycarbonylbutoxy, 3-methoxycarbonyl-1-methylpropoxy,1-methoxycarbonyl-1-methylethoxy, t-butoxycarbonylmethoxy,3-(t-butoxycarbonyl)propoxy and 1-(t-butoxycarbonyl)-1-methylethoxygroups, (h) the carbamoylmethoxy, 2-carbamoylethoxy and4-carbamoylbutoxy groups, (i) the methylaminocarbonylmethoxy,2-propylaminocarbonylethoxy, 3-(N,N-dimethylaminocarbonyl)propoxy,4-N-methyl-N-ethylaminocarbonyl)butoxy and3-(N,N-dipentylaminocarbonyl)-1-methylpropoxy groups, (j) thephenylaminocarbonylmethoxy, 2-phenylaminocarbonylethoxy,3-phenylaminocarbonylpropoxy, 4-phenylaminocarbonylbutoxy and3-phenylaminocarbonyl-1-methylpropoxy groups, (k) the4-methylphenylaminocarbonylmethoxy and2-(4-propylphenylaminocarbonyl)ethoxy groups, (1) the3-(3-ethoxyphenylaminocarbonyl)propoxy and4-(3-butoxyphenylaminocarbonyl)butoxy groups, (m) the4-chlorophenylaminocarbonylmethoxy and3-(4-fluorophenylaminocarbonyl)-1-methylpropoxy groups, (n) the1-pyrrolidinylcarbonylmethoxy, piperidinocarbonylmethoxy,morpholinocarbonylmethoxy, 2-(piperazinylcarbonyl)ethoxy,2-(piperidinocarbonyl)ethoxy and 4-(morpholinocarbonyl)butoxy groups,(o) the N-methylpiperazinylcarbonylmethoxy group, (p) theN-phenylpiperazinylcarbonylmethoxy group, (q) theN-(4-methylphenyl)piperazinylcarbonylmethoxy group, (r) theN-(3-methoxyphenyl)piperazinylcarbonylmethoxy group and (s) theN-(2-chlorophenyl)piperazinylcarbonylmethoxy group. Where R³ and/or R⁴represents an optionally substituted alkoxy group, this is preferably astraight or branched chain alkoxy group having from 1 to 3 carbon atoms,which is unsubstituted or has one or two substituents, the substituentsbeing selected from the group consisting of:

[1] aryl groups having from 6 to 10 carbon atoms and without anysubstituent on the aromatic ring;

[2] carboxy groups;

[3] straight or branched chain alkoxycarbonyl groups having from 2 to 5carbon atoms;

[4] carbamoyl groups; and

[5] groups of formula --CONR^(6') R^(7') (wherein R^(6') and R^(7'),together with the nitrogen atom to which they are attached, form asaturated heterocyclic ring having from 5 to 7 ring atoms, which maycontain an additional oxygen or nitrogen atom in the ring, and which hasno substituents.

R³ more preferably represents a methoxy, benzyloxy, carboxymethoxy,3-carboxypropoxy, 1-carboxy-1-methylethoxy, methoxycarbonylmethoxy,3-methoxycarbonylpropoxy, 1-methoxycarbonyl-1-methylethoxy,t-butoxycarbonylmethoxy, 3-(t-butoxycarbonyl)propoxy,1-(t-butoxycarbonyl)-1-methylethoxy, carbamoylmethoxy,piperidinocarbonylmethoxy or morpholinocarbonylmethoxy group, and mostpreferably represents a methoxy, benzyloxy, carboxymethoxy,3-carboxypropoxy or 1-carboxy-1-methylethoxy group. R⁴ more preferablyrepresents a carboxymethoxy, benzyloxy, 3-carboxypropoxy,1-carboxy-1-methylethoxy, methoxycarbonylmethoxy,3-methoxycarbonylpropoxy, 1-methoxycarbonyl-1-methylethoxy,t-butoxycarbonylmethoxy, 3-(t-butoxycarbonyl)propoxy or1-(t-butoxycarbonyl)-1-methylethoxy group, and most preferably acarboxymethoxy, 3-carboxypropoxy or 1-carboxy-1-methylethoxy group.

Where R³ and/or R⁴ represents a halogen atom, this may preferably be achlorine, fluorine or bromine atom. In this case, R³ and/or R⁴preferably represents a chlorine or fluorine atom, and most preferably afluorine atom.

Where V represents an alkylcarbonyl group, this may be a straight orbranched chain alkylcarbonyl group having from 2 to 6 carbon atoms suchas, for example, an acetyl, propionyl, butyryl or hexanoyl group. Inthis case, V preferably represents a straight or branched chainalkylcarbonyl group having from 2 to 4 carbon atoms, and most preferablyan acetyl group.

Where V represents an arylcarbonyl group, it may be an arylcarbonylgroup having from 7 to 11 carbon atoms, i.e. the aryl group itself(without substituents) has from 6 to 10 carbon atoms, and examplesinclude the benzoyl, 1-naphthoyl and 2-naphthoyl groups. Such groups maybe substituted or unsubstituted and, if substituted, may have one ormore, preferably from 1 to 5, of substituents (a), as defined andexemplified above. Examples of such groups which may be represented by Vinclude: (a) the benzoyl, 1-naphthoyl and 2-naphthoyl groups; (b) the4-methylbenzoyl, 2-propylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl,4-methyl-1-naphthoyl and 4-propyl-2-naphthoyl groups; (c) the2-methoxybenzoyl, 4-ethoxybenzoyl, 4-butoxybenzoyl,4-isopentyloxybenzoyl and 4-methoxy-1-naphthoyl groups; and (d) the3-chlorobenzoyl, 4-fluorobenzoyl, 4-bromobenzoyl and4-chloro-2-naphthoyl groups. Where V represents an arylcarbonyl group,this is more preferably an arylcarbonyl group having from 7 to 11 carbonatoms whose aryl moiety has no substituents, and most preferably abenzoyl group.

Where V represents an alkyl group, this may be a straight or branchedchain alkyl group having from 1 to 5 carbon atoms and optionallysubstituted by one or more of substituents (d). Although there is noparticular limitation on the number of substituents on the alkyl group,from one to three substituents are preferred. Examples of theunsubstituted groups include the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,2-methylbutyl and 1-ethylpropyl groups. The substituted group may be anyof these unsubstituted groups but substituted by one or more ofsubstituents (d). Examples of the substituents include:

(1) carboxy groups; and

(2) straight and branched chain alkoxycarbonyl groups having from 2 to 6carbon atoms such as the methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl and1-ethylpropoxycarbonyl groups.

Examples of such substituted and unsubstituted groups which may berepresented by V include: (a) the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,2-methylbutyl and 1-ethylpropyl groups, (b) the carboxymethyl,2-carboxyethyl, 3-carboxypropyl, 3-carboxybutyl,3-carboxy-1-methylpropyl and 1-carboxy-1-methylethyl groups, and (c) themethoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl,3-ethoxycarbonylpropyl, 2-propoxycarbonylethyl,3-pentyloxycarbonylpropyl, 4-butoxycarbonylbutyl,3-methoxycarbonyl-1-methylpropyl, 1-methoxycarbonyl-1-methylethyl,t-butoxycarbonylmethyl, 3-(t-butoxycarbonyl)propyl and1-(t-butoxycarbonyl)-1-methylethyl groups.

The symbol n represents an integer of from 1 to 3, and is preferably 1or 2, and most preferably 1.

The compounds of the present invention can form salts with bases. Thereis no particular restriction on the nature of these salts, providedthat, where they are intended for therapeutic use, they arepharmaceutically acceptable. Where they are intended for non-therapeuticuses, e.g. as intermediates in the preparation of other, and possiblymore active, compounds, even this restriction does not apply. Examplesof such salts include: salts with an alkali metal, such as sodium,potassium or lithium; salts with an alkaline earth metal, such as bariumor calcium; salts with another metal, such as magnesium or aluminum;organic base salts, such as a salt with dicyclohexylamine; and saltswith a basic amino acid, such as lysine or arginine. Depending on thenature of the substituent groups, the compounds of the present inventionmay contain one or more, e.g. one, two or three carboxy groups, and,accordingly, where the cation is monobasic, the salts may be a mono-,di- or tri-salt. Pharmaceutically acceptable salts are preferred.

The compounds of the present invention have an asymmetric carbon atom atthe 2-position of the chroman ring and can thus form optical isomers.They also have a double bond in the benzylidene moiety and can thereforeform geometrical isomers. Moreover, certain of the substituent groupsmay contain one or more asymmetric carbon atoms in their molecules, andcan thus form optical isomers. Although these are all represented hereinby a single molecular formula, the present invention includes both theindividual, isolated isomers and mixtures, including racemates thereof.Where stereospecific synthesis techniques are employed or opticallyactive compounds are employed as starting materials, individual isomersmay be prepared directly; on the other hand, if a mixture of isomers isprepared, the individual isomers may be obtained by conventionalresolution techniques. In the process, method and composition of theinvention, the individual isomers or a mixture of isomers may be used.

In addition, all of the compounds of the present invention may exist inthe form of tautomers, as represented below [in which, for the sake ofclarity, only the thiazolidinedione or equivalent part of the moleculeis shown, the remainder being as in formula (I)]: ##STR3##

Each of these tautomers individually forms a part of this invention,although all are represented herein by a single formula, and, inpractice, any specific compound may normally be expected to be a mixtureof all tautomers.

The preferred compounds of the present invention are those compounds offormula (I) in which:

(i) R¹ represents a hydrogen atom or a straight or branched chain alkylgroup having from 1 to 10 carbon atoms.

(ii) R² represents a hydrogen atom or a straight or branched chain alkylgroup having from 1 to 10 carbon atoms.

(iii) R³ and R⁴ are the same or different and each represents:

(A) a hydrogen atom;

(B) a straight or branched chain alkyl group having from 1 to 10 carbonatoms;

(C) a formyl group;

(D) a straight or branched chain alkylcarbonyl group having from 2 to 11carbon atoms;

(E) an arylcarbonyl group having from 7 to 11 carbon atoms which isunsubstituted or has from one to five substituents, the substituentsbeing selected from the group consisting of (1) alkyl groups having from1 to 5 carbon atoms, (2) alkoxy groups having from 1 to 5 carbon atomsand (3) halogen atoms;

(F) a carboxy group;

(G) a straight or branched chain alkoxycarbonyl group having from 2 to 7carbon atoms;

(H) an aryloxycarbonyl group having from 7 to 11 carbon atoms;

(I) a hydroxy group;

(J) a straight or branched chain alkylcarbonyloxy group having from 2 to11 carbon atoms;

(K) an arylcarbonyloxy group having from 7 to 11 carbon atoms, whosearyl moiety is unsubstituted or has from one to five substituents, thesubstituents being selected from the group consisting of

(1) straight or branched chain alkyl groups having from 1 to 5 carbonatoms,

(2) straight or branched chain alkoxy groups having from 1 to 5 carbonatoms and

(3) halogen atoms;

(L) a straight or branched chain alkoxy group having from 1 to 5 carbonatoms which is unsubstituted or has from one to three substituents, thesubstituents being selected from the group consisting of

(1) aryl groups having from 6 to 10 carbon atoms which themselves areunsubstituted or have from one to five substituents on the aromaticring, the substituents being selected from the group consisting of (a)straight or branched chain alkyl groups having from 1 to 5 carbon atoms,(b) straight or branched chain alkoxy groups having from 1 to 5 carbonatoms and (c) halogen atoms,

(2) carboxy groups,

(3) straight or branched chain alkoxycarbonyl groups having from 2 to 6carbon atoms,

(4) groups of formula --CONR⁶ R⁷, wherein R⁶ and R⁷ are the same ordifferent and each represents

[1] a hydrogen atom,

[2] a straight or branched chain alkyl group having from 1 to 5 carbonatoms,

[3] an aryl group having from 6 to 10 carbon atoms which isunsubstituted or has from one to five substituents on the aromatic ring,the substituents being selected from the group consisting of (i)straight or branched chain alkyl groups having from 1 to 5 carbon atoms,(ii) straight or branched chain alkoxy groups having from 1 to 5 carbonatoms and (iii) halogen atoms, or

[4] R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a saturated heterocyclic group having from 3 to 7 ringatoms, of which 1 is said nitrogen atom and 0 or 1 is an additionaloxygen or nitrogen atom, the group being unsubstituted or beingsubstituted by at least one substituent, the substituent being selectedfrom the group consisting of (i) straight or branched chain alkyl groupshaving from 1 to 5 carbon atoms and (ii) aryl groups having from 6 to 10carbon atoms, which themselves are unsubstituted or are substituted byfrom 1 to 5 substituents, the substituents being selected from the groupconsisting of (a) straight or branched chain alkyl groups having from 1to 5 carbon atoms, (b) straight or branched chain alkoxy groups havingfrom 1 to 5 carbon atoms and (c) halogen atoms; or

(M) a halogen atom.

(iv) R⁵ represents a hydrogen atom or a straight or branched chain alkylgroup having from 1 to 10 carbon atoms.

(v) W represents a methylene group, a carbonyl group, or a group offormula >C═N--OV, wherein V represents:

(1) a hydrogen atom,

(2) a straight or branched chain alkylcarbonyl group having from 2 to 6carbon atoms,

(3) an arylcarbonyl group having from 7 to 11 carbon atoms, or

(4) a straight or branched chain alkyl group having from 1 to 5 carbonatoms, said group being unsubstituted or being substituted by from oneto three substituents, the substituents being selected from the groupconsisting of

[1] carboxy groups and

[2] straight or branched chain alkoxycarbonyl groups having from 2 to 6carbon atoms.

(vi) n is 1 or 2.

In particular, of these, we prefer those compounds of formula (I) inwhich R¹ is as defined in (i) above; R² is as defined in (ii) above; R³and R⁴ are as defined in (iii) above; R⁵ is as defined in (iv) above; Wis as defined in (v) above; and n is as defined in (vi) above.

The more preferred compounds of the present invention are thosecompounds of formula (I) in which:

(vii) R¹ represents a hydrogen atom or a straight or branched chainalkyl group having from 1 to 4 carbon atoms.

(viii) R² represents a hydrogen atom or a straight or branched chainalkyl group having from 1 to 4 carbon atoms.

(ix) R³ and R⁴ are the same or different and each represents:

(A) a hydrogen atom;

(B) a straight or branched chain alkyl group having from 1 to 4 carbonatoms;

(C) a straight or branched chain alkylcarbonyl group having from 2 to 7carbon atoms;

(D) an arylcarbonyl group having from 7 to 11 carbon atoms and whosearyl moiety is unsubstituted;

(E) a carboxy group;

(F) a straight or branched chain alkoxycarbonyl group having from 2 to 5carbon atoms;

(G) a hydroxy group;

(H) a straight or branched chain alkylcarbonyloxy group having from 2 to7 carbon atoms;

(I) an arylcarbonyloxy group having from 7 to 11 carbon atoms and whosearyl moiety is unsubstituted,

(J) a straight or branched chain alkoxy group having from 1 to 3 carbonatoms, said group being unsubstituted or being substituted by one or twosubstituents, the substituents being selected from the group consistingof

[1] aryl groups having from 6 to 10 carbon atoms and whose aryl moietyis unsubstituted,

[2] carboxy groups,

[3] straight or branched chain alkoxycarbonyl groups having from 2 to 5carbon atoms,

[4] carbamoyl groups, and

[5] groups of formula --CONR^(6') R^(7'), wherein R^(6') and R^(7'),together with nitrogen atom to which they are attached, form a saturatedheterocyclic group having from 3 to 7 ring atoms, of which 1 is saidnitrogen atom and 0 or 1 is an additional oxygen or nitrogen atom, thegroup being unsubstituted; and

(K) halogen atoms.

(x) R⁵ represents a hydrogen atom or a straight or branched chain alkylgroup having from 1 to 4 carbon atoms;

(xi) W represents a methylene group or a group of formula >C═N--OV

wherein V represents:

(1) a hydrogen atom,

(2) a straight or branched chain alkylcarbonyl group having from 2 to 4carbon atoms, or

(3) a benzoyl group.

In particular, of these, we prefer those compounds of formula (I) andsalts thereof in which R¹ is as defined in (vii) above, R² is as definedin (viii) above, R³ and R⁴ are as defined in (ix) above, R⁵ is asdefined in (x) above, W is as defined in (xi) above, and n is as definedin (vi) above.

Still more preferred compounds of the present invention of the generalformula (I) are those in which:

(xii) R¹ represents a hydrogen atom or a methyl, ethyl, propyl,isopropyl, butyl or isobutyl group.

(xiii) R² represents a hydrogen atom or a methyl, ethyl, propyl,isopropyl, butyl or isobutyl group.

(xiv) R³ represents a hydrogen atom, a methyl, ethyl, propyl, isopropyl,butyl or isobutyl group, a straight or branched chain alkylcarbonylgroup having from 2 to 5 carbon atoms, a benzoyl group, a carboxy group,a straight or branched chain alkoxycarbonyl group having from 2 to 5carbon atoms, a hydroxy group, a straight or branched chainalkylcarbonyloxy group having from 2 to 5 carbon atoms, a benzoyloxy,methoxy, benzyloxy, carboxymethoxy, 3-carboxypropoxy,1-carboxy-1-methylethoxy, methoxycarbonylmethoxy,3-methoxycarbonylpropoxy, 1-methoxycarbonyl-1-methylethoxy,t-butoxycarbonylmethoxy, 3-(t-butoxycarbonyl)propoxy,1-(t-butoxycarbonyl)-1-methylethoxy, carbamoylmethoxy,piperidinocarbonylmethoxy or morpholinocarbonylmethoxy group, or achlorine or fluorine atom.

(xv) R⁴ represents a hydrogen atom, a methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or t-butyl group, a straight or branchedchain alkylcarbonyl group having from 2 to 5 carbon atoms, a benzoylgroup, a hydroxy group, a straight or branched chain alkylcarbonyloxygroup having from 2 to 5 carbon atoms, an arylcarbonyloxy group havingfrom 7 to 11 carbon atoms and whose aryl moiety is unsubstituted, acarboxymethoxy, 3-carboxypropoxy, 1-carboxy-1-methylethoxy,methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy,1-methoxycarbonyl-1-methylethoxy, t-butoxycarbonylmethoxy,3-(t-butoxycarbonyl)propoxy or 1-(t-butoxycarbonyl)-1-methylethoxygroup, or a chlorine or fluorine atom.

(xvi) R⁵ represents a hydrogen atom, or a methyl, ethyl, propyl,isopropyl, butyl or isobutyl group.

(xvii) W represents a methylene group or a group of formula >C═N--OV,wherein V represents a hydrogen atom or an acetyl group.

In particular, of these, we prefer those compounds of formula (I) andsalts thereof in which R¹ is as defined in (xii) above, R² is as definedin (xiii) above, R³ is as defined in (xiv) above, R⁴ is as defined in(xv) above, R⁵ is as defined in (xvi) above, W is as defined in (xvii)above, and n is as defined in (vi) above.

The most preferred compounds of the present invention are thosecompounds of formula (I) in which:

(xviii) R¹ represents a methyl group.

(xix) R² represents a hydrogen atom or a methyl group.

(xx) R³ represents a hydrogen atom, a methyl, acetyl, carboxy,methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, hydroxy, acetoxy,methoxy, benzyloxy, carboxymethoxy or 3-carboxypropoxy group, or afluorine atom;

(xxi) R⁴ represents a hydrogen atom, a methyl, t-butyl, acetyl, hydroxy,acetoxy, benzoyloxy, carboxymethoxy, 3-carboxypropoxy or1-carboxy-1-methylethoxy group or a fluorine atom;

(xxii) R⁵ represents a hydrogen atom or a methyl group.

(xxiii) W represents a methylene group.

(xxiv) n is 1.

In particular, of these, we prefer those compounds of formula (I) andsalts thereof in which R¹ is as defined in (xviii) above, R² is asdefined in (xix) above, R³ is as defined in (xx) above, R⁴ is as definedin (xxi) above, R⁵ is as defined in (xxii) above, W is as defined in(xxiii) above, and n is as defined in (xxiv) above.

Specific examples of compounds of the present invention are shown by thefollowing formulae (I-1) and (I-2), in which the substituent groups areas defined by the corresponding one of Tables 1 and 2, i.e. formula(I-1) relates to Table 1 and formula (I-2) relates to Table 2. In theTables, the following abbreviations are used:

    ______________________________________                                        Ac              acetyl                                                        Boz             benzoyl                                                       Bu              butyl                                                          ##STR4##       isobutyl                                                       ##STR5##       t-butyl                                                        ##STR6##       isobutyl                                                      Bz              benzyl                                                        Car             carbamoyl                                                     Dc              decyl                                                         Et              ethyl                                                         Fo              formyl                                                        Me              methyl                                                        Mec             methoxycarbonyl                                               Mor             morpholino                                                    Npo             naphthoyl                                                     Oc              octyl                                                         Ph              phenyl                                                        Pip             piperidyl                                                     Piv             pivaloyl                                                      Pr              propyl                                                        Prn             propionyl                                                     Pyrd            pyrrolidinyl                                                  Tmb             1,1,3,3-tetramethylbutyl                                      Va              valeryl                                                        ##STR7##                     (I-1)                                            ##STR8##                     (I-2)                                           ______________________________________                                    

                                      TABLE 1                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1                                                                             R.sup.2                                                                          R.sup.3      R.sup.4    R.sup.5                                                                          W   -n                                 __________________________________________________________________________    1-1                                                                              H     H  H            H          H  CH.sub.2                                                                         1                                   1-2                                                                              Me    H  H            H          H  CH.sub.2                                                                         1                                   1-3                                                                              Me    H  H            H          H  CH.sub.2                                                                         2                                   1-4                                                                              Me    H  F            H          H  CH.sub.2                                                                         1                                   1-5                                                                              Me    H  Cl           H          H  CH.sub.2                                                                         1                                   1-6                                                                              Me    H  H            F          H  CH.sub.2                                                                         1                                   1-7                                                                              Me    Me H            Me         H  CH.sub.2                                                                         1                                   1-8                                                                              Me    Me Me           Me         Me CH.sub.2                                                                         1                                   1-9                                                                              Me    H  H            HO         Me CH.sub.2                                                                         1                                   1-10                                                                             Me    H  H            HO         Me CH.sub.2                                                                         2                                   1-11                                                                             Me    H  H            HOOCCH.sub.2 O                                                                           Me CH.sub.2                                                                         1                                   1-12                                                                             Me    H  H            HOOCCH.sub.2 O                                                                           Me CO 1                                   1-13                                                                             Me    H  H            AcO        Me CH.sub.2                                                                         1                                   1-14                                                                             Me    H  H            AcO        Me CO 1                                   1-15                                                                             Me    H  H            BozO       Me CH.sub.2                                                                         1                                   1-16                                                                             Me    H  H            BozO       Me CO 1                                   1-17                                                                             Me    H  H            3-HOOC--PrO                                                                              Me CH.sub.2                                                                         1                                   1-18                                                                             Me    H  H            3-EtOOC--PrO                                                                             Me CH.sub.2                                                                         1                                   1-19                                                                             Me    H  H            HOOC--C(Me).sub.2 --O--                                                                  Me CH.sub.2                                                                         1                                   1-20                                                                             Me    H  H            Mec-C(Me).sub.2 --O--                                                                    Me CH.sub.2                                                                         1                                   1-21                                                                             Me    H  H            Car-CH.sub.2 O--                                                                         Me CH.sub.2                                                                         1                                   1-22                                                                             Me    H  H            diMeCar-CH.sub.2 O--                                                                     Me CH.sub.2                                                                         1                                   1-23                                                                             Me    H  H            1-Pyrd-CO--CH.sub.2 O--                                                                  Me CH.sub.2                                                                         1                                   1-24                                                                             Me    H  H            3-(1-Pip-CO)PrO--                                                                        Me CH.sub.2                                                                         1                                   1-25                                                                             Me    H  H            3-(Mor-CO)PrO--                                                                          Me CH.sub.2                                                                         1                                   1-26                                                                             Me    H  HO           H          H  CH.sub.2                                                                         1                                   1-27                                                                             Me    Me HO           Me         Me CH.sub.2                                                                         1                                   1-28                                                                             Me    Me HO           Me         Me CH.sub.2                                                                         2                                   1-29                                                                             Me    Me HO           Me         Me CO 1                                   1-30                                                                             Me    H  HO            .sub.- tBu                                                                              H  CH.sub.2                                                                         1                                   1-31                                                                             Me    H  HO           Tmb        H  CH.sub.2                                                                         1                                   1-32                                                                              .sub.- iBu                                                                         Me HO           Me         Me CH.sub.2                                                                         1                                   1-33                                                                              .sub.- iBu                                                                         Me HO           Me         Me CO 1                                   1-34                                                                             Oc    Me HO           Me         Me CH.sub.2                                                                         1                                   1-35                                                                             Dc    Me HO           Me         Me CH.sub.2                                                                         1                                   1-36                                                                             3,7-diMeOc                                                                          Me HO           Me         Me CH.sub.2                                                                         1                                   1-37                                                                             Me    Me AcO          Me         Me CH.sub.2                                                                         1                                   1-38                                                                             Me    Me AcO          Me         Me CO 1                                   1-39                                                                             Me    Me BozO         Me         Me CH.sub.2                                                                         1                                   1-40                                                                             Me    Me MeO          Me         Me CH.sub.2                                                                         1                                   1-41                                                                             Me    Me BzO          Me         Me CH.sub.2                                                                         1                                   1-42                                                                             Me    Me PrO          Me         Me CH.sub.2                                                                         1                                   1-43                                                                             H     H  HOOCCH.sub.2 O                                                                             H          H  CH.sub.2                                                                         1                                   1-44                                                                             Me    H  HOOC(CH.sub.2).sub.3 O                                                                      .sub.- tBu                                                                              H  CH.sub.2                                                                         1                                   1-45                                                                             Me    Me HOOCCH.sub.2 O                                                                             Me         Me CH.sub.2                                                                         1                                   1-46                                                                             Me    Me HOOCCH.sub.2 O                                                                             Me         Me CO 1                                   1-47                                                                             Me    Me EtOOCCH.sub.2 O                                                                            Me         Me CH.sub.2                                                                         1                                   1-48                                                                             Me    Me HOOC(CH.sub.2).sub.3 O                                                                     Me         Me CH.sub.2                                                                         1                                   1-49                                                                             Me    Me HOOC(CH.sub.2).sub.3 O                                                                     Me         Me CH.sub.2                                                                         2                                   1-50                                                                             Me    Me EtOOC(CH.sub.2).sub.3 O                                                                    Me         Me CH.sub.2                                                                         1                                   1-51                                                                             Me    Me  .sub.- tBuOOC(CH.sub.2).sub.3 O                                                           Me         Me CH.sub.2                                                                         1                                   1-52                                                                             Me    Me HOOCC(Me).sub.2 O                                                                          Me         Me CH.sub.2                                                                         1                                   1-53                                                                             Me    Me EtOOCC(Me).sub.2 O                                                                         Me         Me CH.sub.2                                                                         1                                   1-54                                                                             Me    Me  .sub.- tBuOOCC(Me).sub.2 O                                                                Me         Me CH.sub.2                                                                         1                                   1-55                                                                             H     H  CarCH.sub.2 O                                                                              Me         H  CH.sub.2                                                                         1                                   1-56                                                                             Me    Me CarCH.sub.2 O                                                                              Me         Me CH.sub.2                                                                         1                                   1-57                                                                             Me    Me CarCH.sub.2 O                                                                              Me         Me CH.sub.2                                                                         2                                   1-58                                                                             Me    Me CarCH.sub.2 O                                                                              Me         Me CO 1                                   1-59                                                                             Me    Me diMeCarCH.sub.2 O                                                                          Me         Me CH.sub.2                                                                         1                                   1-60                                                                             Me    Me 1-Pyrd-CO--CH.sub.2 O--                                                                    Me         Me CH.sub.2                                                                         1                                   1-61                                                                             Me    Me 1-Pip-CO--CH.sub.2 O--                                                                     Me         Me CH.sub.2                                                                         1                                   1-62                                                                             Me    Me Mor-CO--CH.sub.2 O--                                                                       Me         Me CH.sub.2                                                                         1                                   1-63                                                                             Me    Me Mor-CO--CH.sub.2 O--                                                                       Me         Me CO 1                                   1-64                                                                             Me    Me Car(CH.sub.2).sub.3 O--                                                                    Me         Me CH.sub.2                                                                         1                                   1-65                                                                             Me    Me  .sub.-- N-EtCar(CH.sub.2).sub.3 O--                                                       Me         Me CH.sub.2                                                                         1                                   1-66                                                                             Me    Me  .sub.-- N-Bu- .sub.-- N-MeCar(CH.sub.2).sub.3 O--                                         Me         Me CH.sub.2                                                                         1                                   1-67                                                                             Me    Me Mor-CO--(CH.sub.2).sub.3 O--                                                               Me         Me CH.sub.2                                                                         1                                   1-68                                                                             Me    Me CarC(Me).sub.2 O--                                                                         Me         Me CH.sub.2                                                                         1                                   1-69                                                                             Me    Me 1-Pyrd-CO--C(Me).sub.2 O--                                                                 Me         Me CH.sub.2                                                                         1                                   1-70                                                                             Me    H  HOOC--       H          H  CH.sub.2                                                                         1                                   1-71                                                                             Me    H  EtOOC--      H          H  CH.sub.2                                                                         1                                   1-72                                                                             Me    H   .sub.- tBuOOC--                                                                           H          H  CH.sub.2                                                                         1                                   1-73                                                                             Me    H  PhOOC--      HOOC--     H  CH.sub.2                                                                         1                                   1-74                                                                             Me    H  H            HOOC--     H  CH.sub.2                                                                         1                                   1-75                                                                             Me    Me Fo           Me         Me CH.sub.2                                                                         1                                   1-76                                                                             Me    H  Ac           HO         Me CH.sub.2                                                                         1                                   1-77                                                                             Me    H  Ac           HO         Me CO 1                                   1-78                                                                             Me    H  Prn          HO         Me CH.sub.2                                                                         1                                   1-79                                                                             Me    H   .sub.- iByr HO         Me CH.sub.2                                                                         1                                   1-80                                                                             Me    H  Piv          HO         Me CH.sub.2                                                                         1                                   1-81                                                                             Me    H  Boz          HO         Me CH.sub.2                                                                         1                                   1-82                                                                             Me    H  1-Npo        HO         Me CH.sub.2                                                                         1                                   1-83                                                                             Me    H  Ac           AcO        Me CH.sub.2                                                                         1                                   1-84                                                                             Me    H  Ac           BozO       Me CH.sub.2                                                                         1                                   1-85                                                                             Me    H  Ac           1-NpoO     Me CH.sub.2                                                                         1                                   1-86                                                                             Me    H  Boz          AcO        Me CH.sub.2                                                                         1                                   1-87                                                                             Me    H    -p-MeBoz   PrnO       Me CH.sub.2                                                                         1                                   1-88                                                                             Me    H   .sub.-- m-ClBoz                                                                           HO         Me CH.sub.2                                                                         1                                   1-89                                                                             Me    H   -o-MeOBoz   HO         Me CH.sub.2                                                                         1                                   1-90                                                                             Me    H  HO           Ac         H  CH.sub.2                                                                         1                                   1-91                                                                             Me    H  HO           Ac         H  CO 1                                   1-92                                                                             Me    H  HO           Boz        H  CH.sub.2                                                                         1                                   1-93                                                                             Me    H  AcO          Ac         H  CH.sub.2                                                                         1                                   1-94                                                                             Me    H  BozO         Ac         H  CH.sub.2                                                                         1                                   1-95                                                                             Me    H  HOOCCH.sub.2 O--                                                                           Ac         H  CH.sub.2                                                                         1                                   1-96                                                                             Me    H  HOOC(CH.sub.2).sub.3 O--                                                                   Ac         H  CH.sub.2                                                                         1                                   1-97                                                                             Me    H  HOOCC(Me).sub.2 O--                                                                        Ac         H  CH.sub.2                                                                         1                                   1-98                                                                             Me    Me  .sub.- tBuOOCC(Me).sub.2 O--                                                              Me         Me CH.sub.2                                                                         1                                   __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1                                                                          R.sup.2                                                                          R.sup.3   R.sup.4   R.sup.5                                                                          V                                             __________________________________________________________________________    2-1                                                                              H  H  H         H         H  H                                             2-2                                                                              Me H  H         H         H  H                                             2-3                                                                              Me Me Me        Me        Me H                                             2-4                                                                              Me H  Cl        H         H  H                                             2-5                                                                              Me Me HO        Me        Me H                                             2-6                                                                              Me Me HO        Me        Me Ac                                            2-7                                                                              Me Me HO        Me        Me Va                                            2-8                                                                              Me H  HO         .sub.- tBu                                                                             H  Boz                                           2-9                                                                              Me Me AcO       Me        Me Me                                            2-10                                                                             Me Me PrO       Me        Me Pr                                            2-11                                                                             Me Me HO        Me        Me HOOCCH.sub.2 --                               2-12                                                                             Me Me HO        Me        Me MeOOCCH.sub.2 --                              2-13                                                                             Et H  BozO      Me        Me MeOOCCH.sub.2 --                              2-14                                                                             Me Me HO        Me        Me EtOOCCH.sub.2 --                              2-15                                                                             Me Me HO        Me        Me  .sub.- tBuOOCCH.sub.2 --                     2-16                                                                             Me Me HO        Me        Me HOOC(CH.sub.2).sub.3 --                       2-17                                                                             Bu H  MeO       Tmb       H  MeOOC(CH.sub.2).sub.3 --                      2-18                                                                             Me Me HO        Me        Me EtOOC(CH.sub. 2).sub.3 --                     2-19                                                                             Me Me HO        Me        H   .sub.- tBuOOC(CH.sub.2).sub.3 --             2-20                                                                             Me Me HOOCCH.sub.2 O--                                                                        Me        Me HOOC(CH.sub.2).sub.3 --                       2-21                                                                             Me Me HOOC(CH.sub.2).sub.3 O--                                                                Me        Me HOOC(CH.sub.2).sub.3 --                       2-22                                                                             Me Me HOOCC(Me).sub.2 O--                                                                     Me        Me HOOCC(Me).sub.2 --                            2-23                                                                             Me H  H         HO        Me H                                             2-24                                                                             Me H  H         AcO       Me Ac                                            2-25                                                                             Me H  H         BozO      Me Boz                                           2-26                                                                             Me H  H         HOOCCH.sub.2 O--                                                                        Me HOOCCH.sub.2 --                               2-27                                                                             Me H  H         EtOOCCH.sub.2 O--                                                                       Me EtOOCCH.sub.2 --                              2-28                                                                             Me H  H         HOOC(CH.sub.2).sub.3 O--                                                                Me HOOC(CH.sub.2).sub.3 --                       2-29                                                                             Me H  H         MeOOC(CH.sub.2).sub.3 O--                                                               Me MeOOC(CH.sub.2).sub.3 --                      2-30                                                                             Me H  H         HOOCC(Me).sub.2 O--                                                                     Me HOOCC(Me).sub.2 --                            2-31                                                                             Me H  H          .sub.- tBuOOCC(Me).sub.2 O--                                                           Me  .sub.- tBuOOCC(Me).sub.2 --                  __________________________________________________________________________

Of the compounds listed above, the following are particularly preferred,that is to say Compounds No. 1-2, 1-4, 1-7, 1-8, 1-9, 1-11, 1-12, 1-27,1-30, 1-32, 1-33, 1-36, 1-37, 1-41, 1-45, 1-48, 1-52, 1-56, 1-61, 1-62,1-70, 1-76 and 2-5. Compounds No.:

1-2. 5-[4-(2-Methylchroman-2-methoxy)benzylidene]-2,4thiazolidinedione;

1-7.5-[4-(2,5,7-Trimethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-8.5-[4-(2,5,6,7,8-Pentamethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-9.5-[4-(7-Hydroxy-2,8-dimethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-27.5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-37.5-[4-(6-Acetoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-41.5-[4-(6-Benzyloxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-45.5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-48.5-{4-[6-(3-Carboxypropoxy)-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4-thiazolidinedione;

1-52.5-{4-[6-(1-Carboxy-1-methylethoxy)-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4-thiazolidinedione;

1-56.5-[4-(6-Carbamoylmethoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

1-61.5-{4-[6-(Piperidinocarbonyl)methoxy-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4-thiazolidinedione;

1-62.5-{4-[6-(Morpholinocarbonyl)methoxy-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4-thiazolidinedione;and

1-70.5-[4-(6-Carboxy-2-methylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione;

being more preferred.

The most preferred compounds are Compounds No. 1-27, 1-37 and 1-41.

The benzylidenethiazolidine compounds of the present invention can beprepared by a variety of methods well known in the art for thepreparation of compounds of this type. Thus, in general terms, thecompounds of formula (I) may be prepared by reacting a compound offormula (II): ##STR9## in which R¹, R², R³, R⁴, R⁵, n and W are asdefined above) with thiazolidine-2,4-dione, which may be represented bythe formula (IIa): ##STR10##

The compound of formula (II), in turn, may be prepared by a variety ofmethods, and the overall sequence of reactions employed in thepreparation of the compounds of the present invention may be illustratedby the following reaction scheme: ##STR11##

In the above formulae, R1, R2 R3, R4, R5, W and n are as defined above;X represents a halogen atom; and Y represents an alkylsulfonyl orarylsulfonyl group, as further defined and exemplified hereafter.

In Step 1 of the above reaction scheme, a compound of formula (IV) isprepared by reducing a compound of formula (III) [which may have beenprepared, for example, as described in the Journal of the American OilChemists' Society, 51, 200 (1974); or Japanese Patent ProvisionalPublication Tokkai No. Sho 60-51189] using a suitable procedure, forexample as described in Japanese Patent Provisional Publication TokkaiNo. Sho 60-51189. In this procedure, the reduction is effected using areducing agent such as lithium aluminum hydride or sodiumbis[2-methoxyethoxy]aluminum hydride (trade name: Vitride). The reactionis preferably carried out in the presence of a solvent. There is noparticular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or on thereagents involved and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: ethers, such asdiethyl ether, tetrahydrofuran and ethylene glycol dimethyl ether;aromatic hydrocarbons, such as benzene, toluene and xylene; aliphatichydrocarbons, such as hexane, heptane, cyclohexane, petroleum ether,ligroin and ethylcyclohexane. There is no particular limitation upon theamount of reducing agent employed, but a slight excess of the reducingagent over the amount of the compound of formula (III) is preferred. Itis more preferred to use from 1 to 2 moles of the reducing agent permole of the compound of formula (III). The reaction can take place overa wide range of temperatures, and the precise reaction temperature isnot critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature of from 10° C. to 120° C. Thetime required for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of the reagentsand solvents employed. However, provided that the reaction is effectedunder the preferred conditions outlined above, a period of from 10minutes to 10 or more hours will usually suffice.

In Step 2 of the above reaction scheme, a compound of formula (V) isprepared by sulfonylation of the compound of formula (IV). This may becarried out by known techniques, for example as described in JapanesePatent Provisional Publication Tokkai No. Sho 63-139182. Thus, thecompound of formula (IV) is subjected to sulfonylation, for exampleusing a sulfonyl halide of formula Y-X, where Y represents analkylsulfonyl group in which the alkyl part has from 1 to 5 carbon atoms(e.g. a methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl orpentylsulfonyl group) or an arylsulfonyl group in which the aryl part isas defined and exemplified above in relation to the aryl groups includedwithin substituents (b) (especially a phenyl group or a p-tolyl group),and X represents a halogen atom (e.g. a chlorine, fluorine, bromine oriodine atom). Examples of such sulfonylating agents include:alkylsulfonyl halides, such as methylsulfonyl chloride, ethylsulfonylchloride and propylsulfonyl bromide; and arylsulfonyl halides, such asphenylsulfonyl chloride, p-tolylsulfonyl chloride and p-tolylsulfonylbromide. The reaction is preferably carried out in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: halogenatedaliphatic hydrocarbons, such as methylene chloride, 1,2-dichloroethane,chloroform and carbon tetrachloride; ethers, such as diethyl ether,dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran and ethyleneglycol dimethyl ether; aromatic hydrocarbons, such as benzene, tolueneand xylene; water; esters, such as ethyl acetate; amides, especiallyfatty acid amides, such as dimethylformamide; and mixtures of any two ormore of these solvents. The reaction is normally and preferably carriedout in the presence of an inorganic base, such as an alkali metalhydroxide (e.g. sodium hydroxide or potassium hydroxide) or an alkalimetal carbonate (e.g. potassium carbonate or sodium carbonate); or anorganic base, such as an alkylamine (e.g. triethylamine) or aheterocyclic amine (e.g. morpholine, N-ethylpiperidine or pyridine).There is no particular limitation on the ratio of the sulfonyl halide tothe compound of formula (IV), but a slight excess of sulfonyl halide ispreferred. It is more preferred to use from 1 to 2 moles, mostpreferably from 1.0 to 1.5 moles, of the sulfonyl halide per mole of thecompound of formula (IV). The reaction will take place over a wide rangeof temperatures, and the precise reaction temperature chosen is notcritical to the invention. In general, we find it convenient to carryout the reaction at a temperature in the range of from 10° to 100° C.,more preferably from 10° to 50° C. The time required for the reactionmay likewise vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents. However, in mostcases, a period of from a few hours to 10 or more hours will normallysuffice.

In Step 3 of the above reaction scheme, a compound of formula (VI) isprepared by reacting the compound of formula (V) prepared in Step 2 withan alkali metal halide. Examples of alkali metal halides which may beused in this reaction include sodium iodide, sodium bromide andpotassium iodide. The reaction is preferably carried out in the presenceof a solvent. There is no particular restriction on the nature of thesolvent to be employed, provided that it has no adverse effect on thereaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: halogenated aliphatic hydrocarbons, such as methylene chloride,1,2-dichloroethane, chloroform and carbon tetrachloride; ethers, such asdiethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuranand ethylene glycol dimethyl ether; aromatic hydrocarbons, such asbenzene, toluene and xylene; and amides, especially fatty acid amides,such as dimethylformamide. The reaction is preferably carried out byreacting the compound of formula (V) with sodium iodide in the presenceof dimethylformamide. There is no particular limitation upon the ratioof the alkali metal halide to the compound of formula (V), but thereaction is most preferably carried out using from 5 to 30 moles, morepreferably from 10 to 20 moles, of the alkali metal halide per mole ofthe compound of formula (V). The reaction will take place over a widerange of temperatures, and the precise reaction temperature chosen isnot critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature in the range of from 100° to200° C., more preferably from 130° to 180° C. The time required for thereaction may likewise vary widely, depending on many factors, notablythe reaction temperature and the nature of the reagents and solventemployed. However, in most cases, a period of from a few hours to 10 ormore hours will normally suffice.

In Step 4 of the above reaction scheme, a compound of formula (II) isprepared by reacting the compound of formula (VI) prepared as describedin Step 3 with p-hydroxybenzaldehyde, which has the formula (IIIa), forexample as described in Japanese Patent Provisional Publication TokkaiNo. Sho 63-139182. The reaction is preferably carried out in thepresence of a solvent. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: halogenated aliphatic hydrocarbons, such as methylene chloride,1,2-dichloroethane, chloroform and carbon tetrachloride; ethers, such asdiethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuranand ethylene glycol dimethyl ether; aromatic hydrocarbons, such asbenzene, toluene and xylene; water; esters, such as ethyl acetate;amides, especially fatty acid amides, such as dimethylformamide; andmixtures of any two or more of these solvents. The reaction is normallyand preferably carried out in the presence of a base, which may be: aninorganic base, such as an alkali metal hydroxide (e.g. sodium hydroxideor potassium hydroxide), an alkali metal carbonate (e.g. potassiumcarbonate or sodium carbonate) or an alkali metal halide (e.g. sodiumiodide, sodium bromide or potassium bromide); or an organic base, suchas an alkylamine (e.g. triethylamine); or a heterocyclic amine (e.g.morpholine, N-ethylpiperidine or pyridine). There is no particularlimitation on the ratio of the p-hydroxybenzaldehyde to the compound offormula (VI), but the reaction is normally and preferably carried outusing from 1 to 3 moles, more preferably from 1.5 to 2.5 moles, ofp-hydroxybenzaldehyde per mole of the compound of formula (VI). The baseis normally and preferably used in an amount of from 1 to 3 moles, morepreferably from 1.5 to 2.5 moles, per mole of the compound of formula(VI). The reaction will take place over a wide range of temperatures,and the precise reaction temperature chosen is not critical to theinvention. In general, we find it convenient to carry out the reactionat a temperature in the range of from 50° to 200° C., more preferablyfrom 130° to 180° C. The time required for the reaction may likewisevary widely, depending on many factors, notably the reaction temperatureand the nature of the reagents and solvent employed. However, in mostcases, a period of from a few hours to 10 or more hours will normallysuffice.

Step 5 of this reaction scheme provides an alternative to Steps 2 to 4.In Step 5, a compound of formula (II) is prepared directly from thecompound of formula (IV) and p-hydroxybenzaldehyde of formula (IIIa) bya coupling reaction, for example as described in Japanese PatentProvisional Publication Tokkai No. Hei 1-131169. Examples of couplingagents which may be employed in this reaction include diethylazodicarboxylate or triphenylphosphine. The reaction preferably carriedout in the presence of a solvent. There is no particular restriction onthe nature of the solvent to be employed, provided that it has noadverse effect on the reaction or on the reagents involved and that itcan dissolve the reagents, at least to some extent. Examples of suitablesolvents include: halogenated aliphatic hydrocarbons, such as methylenechloride, 1,2-dichloroethane, chloroform or carbon tetrachloride;ethers, such as diethyl ether, dibutyl ether, diisobutyl ether, dioxane,tetrahydrofuran or ethylene glycol dimethyl ether; aromatichydrocarbons, such as benzene, toluene or xylene; esters, such as ethylacetate; amides, especially fatty acid amides, such asdimethylformamide; and mixtures of any two or more of these solvents.There is no particular limitation on the ratio of the compound offormula (IV) to the coupling agent, e.g. diethyl azodicarboxylate ortriphenylphosphine, but it is preferred to use a slight molar excess ofthe coupling agent. We prefer to use from 1 to 2 moles, more preferablyfrom 1.0 to 1.5 moles, of the coupling agent per mole of the compound offormula (IV). The reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. In general, we find it convenient to carry out thereaction at a temperature of from 0° to 70° C. The time required for thereaction may also vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents. However, providedthat the reaction is effected under the preferred conditions outlinedabove, a period of from a few minutes to 10 or more hours will usuallysuffice.

Step 6 of this reaction scheme provides a further alternative to Steps 2to 4. In Step 6, a compound of formula (II) is prepared by reacting thecompound of formula (IV), prepared as described in Step 1, with ap-halobenzaldehyde of formula (IIIb) (particularlyp-fluorobenzaldehyde), which reaction may, for example, be carried outas described in Japanese Patent Provisional Publication Tokkai No. Hei1-131169. The reaction is preferably carried out in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: halogenatedaliphatic hydrocarbons, such as methylene chloride, 1,2-dichloroethane,chloroform or carbon tetrachloride; ethers, such as diethyl ether,dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran or ethyleneglycol dimethyl ether; aromatic hydrocarbons, such as benzene, tolueneor xylene; amides, such as dimethylformamide; sulfoxides, such asdimethyl sulfoxide; and sulfones, such as sulfolane. In general, thereaction is preferably carried out in the presence of a base, which ispreferably an essentially inorganic base, such as an alkali metalcarbonate (e.g. potassium carbonate or sodium carbonate), an alkalimetal hydride (e.g. sodium hydride); an alkali metal acetate (e.g.potassium acetate or sodium acetate); or an alkali metal alkoxide (e.g.sodium methoxide or sodium ethoxide). There is no particular limitationon the ratio of the p-halobenzaldehyde to the compound of formula (IV),but it is preferred to use a slight molar excess of thep-halobenzaldehyde to the compound of formula (Iv). In general, weprefer to use from 1 to 2 moles, more preferably from 1.0 to 1.5 moles,of the p-halobenzaldehyde per mole of the compound of formula (IV). Thereaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from 100° to 170° C. The time required for the reactionmay also vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents and solvents employed.However, provided that the reaction is effected under the preferredconditions outlined above, a period of from a few minutes to 10 or morehours will usually suffice.

Step 7 of this reaction scheme provides an alternative to Steps 3 and 4.In Step 7, a compound of formula (V), prepared as described in Step 2,is reacted with p-hydroxybenzaldehyde of formula (IIIa), for example bythe procedure described in Japanese Patent Provisional PublicationTokkai No. Sho 63-139182 to give a compound of formula (II). Thereaction is essentially the same as that described in Step 4, and may becarried out in a similar manner to the procedure described in Step 4.

Steps 8 and 9 provide a further alternative to Steps 3 and 4.

In Step 8, a compound of formula (V), prepared as described in Step 2,is reacted with a p-halophenol of formula (IVb) to give a compound offormula (VII). The reaction is preferably carried out in the presence ofa solvent. There is no particular restriction on the nature of thesolvent to be employed, provided that it has no adverse effect on thereaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: halogenated aliphatic hydrocarbons, such as methylene chloride,1,2-dichloroethane, chloroform and carbon tetrachloride; ethers, such asdiethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuranand ethylene glycol dimethyl ether; aromatic hydrocarbons, such asbenzene, toluene and xylene; water; esters, such as ethyl acetate;amides, especially fatty acid amides, such as dimethylformamide; andmixtures of any two or more of these solvents. The reaction is normallyand preferably carried out in the presence of a base, which may be: aninorganic base, such as an alkali metal hydroxide (e.g. sodium hydroxideor potassium hydroxide) or an alkali metal carbonate (e.g. potassiumcarbonate or sodium carbonate); or an organic base, such as analkylamine (e.g. triethylamine) or a heterocyclic amine (e.g.morpholine, N-ethylpiperidine or pyridine). There is no particularlimitation on the ratio of the p-halophenol of formula (IVb) to thecompound of formula (V), but it is preferred to use a slight excess ofthe p-halophenol over the compound of formula (V). More preferably thereaction is carried out using from 1 to 2 moles, most preferably from1.0 to 1.5 moles, of the p-halophenol per mole of the compound offormula (V). The reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. In general, we find it convenient to carry out thereaction at a temperature of from 10 to 50° C., more preferably from 15°to 30° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvents employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from a few hours to 10 or more hours will usually suffice.

In Step 9 of this reaction scheme, the compound of formula (II) isprepared by reacting the compound of general formula (VII), prepared asdescribed in Step 8, with butyllithium and dimethylformamide, forexample as described in Japanese Patent Provisional Publication TokkaiNo. Hei 1-186884. The reaction is preferably carried out in the presenceof a solvent. There is no particular restriction on the nature of thesolvent to be employed, provided that it has no adverse effect on thereaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: ethers, such as diethyl ether, dibutyl ether, diisobutyl ether,dioxane, tetrahydrofuran and ethylene glycol dimethyl ether; andaromatic hydrocarbons, such as benzene, toluene and xylene. There is noparticular limitation on the relative molar ratios of the compound offormula (VII), butyllithium and dimethylformamide, but, in general, thereaction is preferably carried out using about one mole of butyllithiumand about one mole of dimethylformamide per mole of the compound offormula (VII). The reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. In general, we find it convenient to carry out thereaction at a temperature of from -70° to -80° C., more preferably about-80° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from a few hours to 10 or more hours will usually suffice.

In Step 10, the desired compound of formula (I) is prepared by reactingthe compound of formula (II), which may have been prepared by any of theroutes outlined above, with 2,4-thiazolidinedione, for example accordingto the procedure described in Japanese Patent Provisional PublicationTokkai No. Sho 63-139182. The reaction is preferably carried out in thepresence of a solvent. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: alcohols, such as methanol, ethanol, propanol, butanol orethylene glycol monomethyl ether; amides, especially fatty acid amides,such as dimethylformamide; sulfoxides, such as dimethyl sulfoxide;sulfones, such as sulfolane; ethers, such as dioxane, ethylene glycoldimethyl ether and tetrahydrofuran; ketones, such as acetone; nitriles,such as acetonitrile; organic acids, such as acetic acid; water; andmixtures of any two or more of these solvents. The reaction is normallyand preferably carried out in the presence of a base, which may be: aninorganic base, such as an alkali metal carbonate (e.g. potassiumcarbonate or sodium carbonate), an alkali metal hydride (e.g. sodiumhydride), an alkali metal acetate (e.g. potassium acetate or sodiumacetate), an alkali metal alkoxide (e.g. sodium methoxide or sodiumethoxide) or ammonia; or an organic base, such as an alkylamine (e.g.methylamine, ethylamine, diethylamine or triethylamine); or aheterocyclic amine (e.g. morpholine, pyrrolidine, piperidine,N-ethylpiperidine, piperazine or pyridine). There is no particularlimitation on the ratio of the compound of formula (II) to the2,4-thiazolidinedione, but the reaction is preferably carried out usingfrom 1 to 4 moles, more preferably from 1 to 2.5 moles, of the2,4-thiazolidinedione per mole of the compound of formula (II) and from0.05 to 1 mole, more preferably from 0.2 to 0.6 mole, of the base permole of the compound o#formula (II). The reaction can take place over awide range of temperatures, and the precise reaction temperature is notcritical to the invention. In general, we find it convenient to carryout the reaction at a temperature of from 40° C. to the refluxtemperature of the reaction mixture, more preferably from 80° to 150° C.The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thereagents. However, provided that the reaction is effected under thepreferred conditions outlined above, a period of from several tens ofminutes to several tens of hours will usually suffice.

Alternatively, the compound of formula (I) may also be prepared byreacting 5-(4-hydroxybenzylidene)-2,4-thiazolidinedione [which may havebeen prepared, for example, as described in J. Med. Chem., 14, 528(1971) or "Nippon Kagaku Zasshi" (the Journal of the Chemical Society ofJapan), 92, 867 (1971)] with the compound of formula (VI), prepared asdescribed in Step 3, or with the compound of formula (V), prepared asdescribed in Step 2. In carrying out this alternative process, thereaction may be carried out in a similar manner and using similarreaction conditions to those described in Step 4 or Step 7,respectively.

In the compounds of formulae (I) through (VII), where R³ and/or R⁴represents a hydroxy group, R³ and/or R⁴ can, if desired, be transformedto an alkylcarbonyloxy group, an arylcarbonyloxy group (which mayoptionally have one or more substituents on the aromatic ring) or analkoxy group (which may optionally have one or more substituents), allas defined above for R³ and/or R⁴, by using the reactions described inthe following optional steps. These reactions can be carried out, forexample, as described in Japanese Patent Provisional Publication TokkaiNo. Sho 62-5980.

Thus, compounds of formulae (I) through (VII) where R³ and/or R⁴represents an alkylcarbonyloxy group or an arylcarbonyloxy group (whosearyl moiety may optionally have one or more substituents) can beprepared by contacting the corresponding compounds wherein R³ and/or R⁴represents a hydroxy group with an acylating agent, which may be analkylcarboxylic or arylcarboxylic acid, or an acid halide or acidanhydride thereof, corresponding to the carbonyloxy group which it isdesired to introduce. The reaction is preferably effected in thepresence of a dehydrating agent or catalyst, such as an inorganic acid(e.g. hydrochloric acid or sulfuric acid) or an organic acid (e.g.-toluenesulfonic acid). The reaction is normally carried out in thepresence of a solvent. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: ethers, such as diethyl ether, tetrahydrofuran and dioxane;aromatic hydrocarbons, such as benzene, toluene and xylene; aliphatichydrocarbons, such as hexane, cyclohexane and heptane; halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride and chloroform; ketones, such as acetone and methylethyl ketone; amides, especially fatty acid amides, such asdimethylformamide; sulfoxides, such as dimethyl sulfoxide; sulfones,such as sulfolane; organic bases, such as pyridine and triethylamine;water; and mixtures of any two or more of these solvents. There is noparticular limitation on the ratio of the starting compound and theacylating agent, but the reaction is preferably carried out using aslight molar excess of the acylating agent, more preferably from 1 to 10moles of the acylating agent per mole of the starting compound. Thereaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from 0° to 100° C. The time required for the reaction mayalso vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents and solvent employed.However, provided that the reaction is effected under the preferredconditions outlined above, a period of from several minutes to 10 ormore hours will usually suffice.

Those compounds of formulae (I) through (VII) where R³ and/or R⁴represents an alkoxy group (which may optionally have one or moresubstituents) may be prepared by contacting the corresponding compoundswherein R³ and/or R⁴ represents a hydroxy group with an alkyl halide(preferably bromide) which may have one or more substituents, preferablyin the presence of a base. The reaction is normally carried out in thepresence of a solvent. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: ethers, such as diethyl ether, tetrahydrofuran or dioxane;aromatic hydrocarbons, such as benzene, toluene and xylene; aliphatichydrocarbons such as hexane, cyclohexane and heptane; halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride and chloroform; ketones, such as acetone and methylethyl ketone; amides, especially fatty acid amides, such asdimethylformamide; sulfoxides, such as dimethyl sulfoxide; sulfones,such as sulfolane; water; and mixtures of any two or more of thesesolvents. Examples of the bases which may be used in this reactioninclude: inorganic bases, such as an alkali metal carbonate (e.g. sodiumcarbonate or potassium carbonate), an alkali metal bicarbonate (e.g.sodium bicarbonate or potassium bicarbonate), an alkali metal hydroxide(e.g. sodium hydroxide or potassium hydroxide), an alkaline earth metalhydroxide (e.g. calcium hydroxide), an alkali metal hydride (e.g. sodiumhydride or potassium hydride), an alkali metal alkoxides (e.g. sodiummethoxide, sodium ethoxide or potassium t-butoxide), an organic lithiumcompound (e.g. butyllithium or t-butyllithium), a lithium dialkylamide(e.g. lithium diisopropylamide or lithium dicyclohexylamide) or ammonia;and organic bases, such as an alkylamine (e.g. methylamine, ethylamine,diethylamine or triethylamine) or a heterocyclic amine (e.g. morpholine,pyrrolidine, piperidine, N-ethylpiperidine, piperazine or pyridine). Theratio of the alkyl halides to the starting compound is preferably from 1to 10 moles of alkyl halide per mole of the starting compound, and theratio of the base to the starting compound is preferably from 1 to 10moles of the base per mole of the starting compound. The reaction cantake place over a wide range of temperatures, and the precise reactiontemperature is not critical to the invention. In general, we find itconvenient to carry out the reaction at a temperature from -10° to 100°C. The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thereagents and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromseveral minutes to several days will usually suffice.

Furthermore, those compounds where R³ and/or R⁴ represents an alkoxygroup which is substituted by a substituted or unsubstituted carbamoylgroup of formula --CONR⁶ R⁷, can be prepared by amidation of thecorresponding compound having a carboxy or alkoxycarbonyl group withammonia or with an amine, by conventional means. Alternatively, acompound wherein R³ and/or R⁴ represents an alkoxy group substitutedwith a carbamoyl group can be prepared from the corresponding compoundwherein R³ and/or R⁴ represents a hydroxy group by reaction of thecompound wherein R³ and/or R⁴ represents a hydroxy group with acarbamoylalkyl halide in the presence of two equivalents of sodiumhydride in dimethylformamide.

Conversely, those compounds of formulae (I) through (VII) where R³and/or R⁴ represents an alkylcarbonyloxy group, an arylcarbonyloxy group(which may optionally have one or more substituents on the aromaticring) or an alkoxy group (which may optionally have one or moresubstituents) can, if desired, be converted to the correspondingcompounds where R³ and/or R⁴ represents a hydroxy group. The reactioncan be carried out, for example, as described in Japanese PatentProvisional Publication Tokkai No. Sho 62-5980. This reaction is aconventional hydrolysis reaction and may be carried out using anyreagent commonly used in the art for this type of reaction, for example:an inorganic acid such as hydrochloric acid, sulfuric acid or nitricacid; or an organic acid such as p-toluenesulfonic acid. The reaction isnormally carried out in the presence of a solvent. There is noparticular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or on thereagents involved and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: alcohols, such asmethanol, propanol or butanol; ethers, such as diethyl ether,tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene,toluene or xylene; aliphatic hydrocarbons, such as hexane, cyclohexaneor heptane; halogenated hydrocarbons, especially halogenated aliphatichydrocarbons, such as methylene chloride or chloroform; ketones, such asacetone or methyl ethyl ketone; amides, especially fatty acid amides,such as dimethylformamide; sulfoxides, such as dimethyl sulfoxide;sulfones, such as sulfolane; organic acids, such as acetic acid orpropionic acid; water; and mixtures of any two or more of thesesolvents. Preferred solvents include water and organic acids, such asacetic acid. The amount of acid used is preferably from 0.001 to 5moles, more preferably from 0.01 to 1 mole, per mole of the startingcompound. The reaction can take place over a wide range of temperatures,and the precise reaction temperature not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from room temperature to 100° C. The time required forthe reaction may also vary widely, depending on many factors, notablythe reaction temperature and the nature of the reagents and solventemployed. However, provided that the reaction is effected under thepreferred conditions outlined above, a period of from several minutes to10 or more hours will usually suffice.

Similarly, where W represents a group of formula C=N--OV (wherein Vrepresents a hydrogen atom, an alkylcarbonyl group, an arylcarbonylgroup or an alkyl group which may optionally have one or moresubstituents), any group or atom represented by V can be converted toany other group or atom so represented by a similar reaction to thosedescribed above in relation to the groups represented by R³ and R⁴.

Thus, when V represents a hydrogen atom, it can be converted to analkylcarbonyl group, an arylcarbonyl group or an alkyl group which mayoptionally be substituted, and conversely when V represents analkylcarbonyl group, an arylcarbonyl group or an alkyl group which mayoptionally be substituted, it can be converted to a hydrogen atom byhydrolysis according to the procedure described above.

Furthermore, in the compounds of formulae (I) through (VII), where R³and/or R⁴ represents a formyl group, an alkylcarbonyl group, anarylcarbonyl group (which may optionally have one or more substituentson the aromatic ring), a carboxy group, an alkoxycarbonyl group, anaryloxycarbonyl group or a halogen atom, these compounds can beconverted into each other, if necessary, by any appropriate combinationof oxidation, reduction, halogenation, hydrolysis or neutralizationaccording to conventional means.

After completion of any or all of the above reactions, the desiredcompounds obtained in any reaction can be separated from the reactionmixture and then purified, if necessary, by conventional means, forexample the various chromatography techniques, notably columnchromatography, recrystallization or reprecipitation. For example, inone suitable recovery procedure, the reaction mixture is mixed with asolvent and extracted with that solvent; the mixture is then freed fromthe solvent by distillation. The resulting residue may be purified bycolumn chromatography through silica gel to yield the desired compoundas a pure specimen.

If required, the resolution of isomers can be carried out byconventional resolution and purification techniques at any appropriatetime.

The benzylidenethiazolidine compounds of formula (I) according to thepresent invention are useful as intermediates for preparing thecorresponding benzylthiazolidine compounds (for example, see JapanesePatent Provisional Publication Tokkai No. Sho 60-51189, No. Sho 62-5980,No. Sho 64-38090 and the like), i.e. compounds of formula (Ia):##STR12## (in which R to R , W and n are as defined above) by reduction,and such a process also forms part of the present invention.

The preparation of the benzylthiazolidine derivatives from thebenzylidenethiazolidine compounds of the present invention may becarried out by means of a conventional reduction of a double bond. Thereaction may be carried out using any reducing agent known to be capableof reducing a double bond without adversely affecting other parts of themolecule.

For example, one suitable reduction reaction comprises contacting thebenzylidenethiazolidine compound with hydrogen in the presence of anoble metal catalyst, which is preferably supported, such as platinum,palladium or rhodium, particularly palladium-on-charcoal. The reactionis normally and preferably carried out in the presence of a solvent.There is no particular restriction on the nature of the solvent to beemployed, provided that it has no adverse effect on the reaction or onthe reagents involved and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: etherst such asdiethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol,ethanol, isopropanol or butanol; aromatic hydrocarbons, such as benzeneor toluene; amides, especially fatty acid amides, such asdimethylformamide or dimethylacetamide; carboxylic acids, such as formicacid, acetic acid or propionic acid; water; and mixtures of any two ormore thereof. Hydrogenation may be carried out under atmosphericpressure or, more preferably, under superatmospheric pressure in aclosed pressure vessel. The amount of catalyst used is preferably from0.01 to 25% by weight of the compound of formula (I). The reaction cantake place over a wide range of temperatures, and the precise reactiontemperature is not critical to the invention. In general, we find itconvenient to carry out the reaction at a temperature of from 0° to 100°C. The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thereagents and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromseveral minutes to 10 or more hours will usually suffice.

An alternative reduction reaction comprises contacting thebenzylidenethiazolidine compound with a metal amalgam, such as sodiumamalgam or aluminum amalgam, particularly sodium amalgam. The reactionis effected in the presence of a solvent. There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or on the reagents involved andthat it can dissolve the reagents, at least to some extent. Examples ofsuitable solvents include: alcohols, such as methanol. The reaction cantake place over a wide range of temperatures, and the precise reactiontemperature is not critical to the invention. In general, we find itconvenient to carry out the reaction at about room temperature. The timerequired for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of the reagentsand solvent employed. However, provided that the reaction is effectedunder the preferred conditions outlined above, a period of from severalminutes to 10 or more hours will usually suffice.

A further alternative reduction method comprises treating thebenzylidenethiazolidine compound with a metal, e.g. zinc, iron or tin inan acid, which may be an inorganic acid (e.g. hydrochloric acid,hydrobromic acid or sulfuric acid) or an organic acid (e.g. aceticacid). The reaction can take place over a wide range of temperatures,and the precise reaction temperature is not critical to the invention.In general, we find it convenient to carry out the reaction at thereflux temperature of the reaction mixture. The time required for thereaction may also vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents. However, providedthat the reaction is effected under the preferred conditions outlinedabove, a period of from several minutes to 10 or more hours will usuallysuffice.

After completion of the reaction, the desired benzylthiazolidinederivatives can be purified by said conventional means, such as columnchromatography, recrystallization, reprecipitation and the like.

The compounds of the present invention exhibited the ability to inhibitthe formation of lipid peroxide in the mammalian body in the test systemdescribed by Malvy et al. [Biochem. Biophys. Res. Commun., 95, 734(1980)]. Accordingly, these compounds may be used for the treatment ofhuman arteriosclerosis and complications thereof.

The compounds of the invention may be administered orally, for examplein the form of tablets, syrups, capsules, powders or granules, orparenterally, for example by injection (intravenous, subcutaneous orintramuscular) or in the form of a suppository. Alternatively, they maybe formulated for topical administration, e.g. to the eyes. For example,for administration to the eye mucosa, it is preferred that the compoundsof the invention should be administered in the form of eye drops or eyeointments, the formulation of which is well known in the art. Dependingupon the nature of the formulation, they may be used alone or inadmixture with one or more conventional adjuvants. Examples includeexcipients, binders, disintegrating agents, lubricants, corrigents,solubilizing agents, suspension aids and coating agents.

The recommended dosage will, of course, vary depending upon the age andbody weight of the patient as well as the nature and severity of thedisease, and the intended route of administration. However, for an adulthuman patient, a daily dose of from 5.0 mg to 2000 mg (which may beadministered in a single dose or in divided doses) is recommended in thetreatment of hyperlipaemia, diabetes mellitus and complications thereof,when administered orally or parenterally.

The invention is further illustrated by the following Examples, whichshow the preparation of certain of the compounds of the presentinvention, and by the subsequent Preparations, of which Preparations 1,2 and 3 show the preparation of some of the starting materials used inthese Examples and Preparations 4, 5 and 6 show the use of the compoundsof the present invention in the preparation of their correspondingbenzyl derivatives. In these Examples and Preparations, the NuclearMagnetic Resonance Spectra were measured in the solvent specified ineach case, scanning at either 60 MHz or 270 MHz, as specified, and usingtetramethylsilane as the internal standard.

EXAMPLE 15-[4-(6-Benzyloxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(Compound No. 1-41)

4.7 g of 2,4-thiazolidinedione and 0.92 g of piperidine were added to asolution of 11.6 g of6-benzyloxy-2-[(4-formylphenyl)oxymethyl]-2,5,7,8-tetramethylchroman(prepared as described in Preparation 3) dissolved in 60 ml of2-methoxyethanol, and the resulting mixture was heated under reflux for1.5 hours. At the end of this time, the reaction mixture was extractedwith methylene chloride. The extract was washed with water, and then thesolvent was removed by distillation under reduced pressure. The residuethus obtained was recrystallized from methanol, to afford 11.2 g of thetitle compound, melting at 190°-193° C. Nuclear Magnetic ResonanceSpectrum (hexadeuterated dimethyl sulfoxide, 60 MHz), δ ppm: 1.33 (3H,singlet); 1.83-2.33 (2H, multiplet); 1.97 (3H, singlet); 2.10 (6H,singlet); 2.40-2.90 (2H, multiplet); 4.07 (2H, singlet); 4.63 (2H,singlet); 7.10 (2H, doublet, J=9 Hz); 7.40 (5H, singlet); 7.47 (2H,doublet, J=9 Hz); 7.73 (1H, singlet).

EXAMPLE 2 5- [4-(6-Acetoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(Compound No. 1-37)

4.74 g of 2,4-thiazolidinedione and 0.92 g of piperidine were added to asolution of 10.3 g of6-acetoxy-2-[(4-formylphenyl)oxymethyl]-2,5,7,8-tetramethylchroman(prepared by a procedure similar to that described in Preparations 1, 2and 3) dissolved in 60 ml of 2-methoxyethanol, and the resulting mixturewas heated under reflux for 1.5 hours. At the end of this time, thereaction mixture was treated in a similar manner to that described inExample 1, to afford 10.0 g of the title compound, melting at203°-205.5° C.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide,60 MHz), δ ppm: 1.40 (3H, singlet); 1.80-2.17 (2H, multiplet); 1.97 (6H,singlet); 2.03 (3H, singlet); 2.30 (3H, singlet); 2.43-2.90 (2H,multiplet); 4.03 (2H, singlet); 7.00 (2H, doublet, J=9 Hz); 7.40 (2H,doublet, J=9 Hz); 7.67 (1H, singlet).

EXAMPLE 35-[(6-Hydroxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedioneCompound No. 1-27)

15 ml of concentrated hydrochloric acid were added to a solution of 15.4g of5-[4-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(prepared as described in Example 1) dissolved in 60 ml of acetic acid,and the resulting mixture was heated under reflux for 1.5 hours. At theend of this time, the reaction mixture was mixed with 200 ml of ethylacetate and 100 ml of water, and the pH was adjusted to a value of 7 bythe addition of a 2N aqueous solution of sodium hydroxide. The ethylacetate layer was separated and was washed with water to removeimpurities, and the aqueous layer was extracted with ethyl acetate toseparate the desired compound. After the same washing and extractionprocedures had been repeated twice, the combined ethyl acetate extractswere concentrated by distillation under reduced pressure. The residuethus obtained was washed with methanol and 11.6 g of the title compoundwere collected by filtration.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide,60 MHz), δ ppm: 1.43 (3H, singlet); 2.10 (6H, singlet); 2.13 (3H,singlet); 2.20-2.43 (2H, multiplet); 2.47-2.90 (2H, multiplet);3.70-5.53 (1H, broad); 4.03 (2H, singlet); 7.03 (2H, doublet, J=9 Hz);7.50 (2H, doublet, J=9 Hz); 7.87 (1H, singlet).

EXAMPLE 45-[4-(6-Acetoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(Compound No. 1-37)

0.71 g of acetic anhydride and 0.55 g of pyridine were added to asolution of 1.5 g of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]2,4-thiazolidinedione(prepared as described in Example 3) dissolved in 7.5 ml of toluene, andthe resulting mixture was stirred at room temperature for 5 hours. Atthe end of this time, the reaction mixture was washed with water, andthe solvent was removed by distillation under reduced pressure. Aftertrituration with methanol, the crystals thus obtained were collected byfiltration to afford 1.2 g of the title compound.

The nuclear magnetic resonance spectrum of this compound was identicalto that of the product of Example 2.

EXAMPLE 55-[4-(6-t-Butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(Compound No. 1-98)

500 mg of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(prepared as described in Example 3) were dissolved in 10 ml ofdimethylformamide, and 220 mg of sodium hydride (as a 55% w/w dispersionin mineral oil) were added to the resulting solution, whilstice-cooling. The resulting mixture was then stirred at room temperaturefor 40 minutes. At the end of this time, the mixture was againice-cooled, and 240 mg of t-butyl bromoacetate were added dropwise toit; it was then stirred for 45 minutes, whilst ice-cooling. At the endof this time, the reaction mixture was poured into water and extractedwith ethyl acetate. The extract was dried over anhydrous sodium sulfateand freed from the solvent by distillation under reduced pressure. Theresidue thus obtained was subjected to column chromatography throughsilica gel, using a 3 : 1 by volume mixture of hexane and ethyl acetateas the eluent, to afford 360 mg of the title compound as a pale yellowpowder, softening at 103°-120° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm: 1.42 (3H,singlet); 1.53 (9H, singlet); 1.85-2.0 (1H, multiplet); 2.05 (3H,singlet); 2.05-2.2 (1H, multiplet); 2.15 (3H, singlet); 2.19 (3H,singlet); 2.62 (2H, broad triplet, J=6 Hz); 3.97 and 4.04 (2H, AB type,J=9 Hz); 4.17 (2H, singlet); 7.02 (2H, doublet, J=9 Hz); 7.44 (2H,doublet, J=9 Hz); 7.80 (1H, singlet); 8.06 (1H, broad singlet).

EXAMPLE 65-[4r(6-Carboxymethoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(Compound No. 1-45)

A mixture of 350 mg of5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(prepared as described in Example 5) and 3 ml of a 4N solution ofhydrogen chloride in dioxane was allowed to stand overnight at roomtemperature. At the end of this time, the reaction mixture was freedfrom the solvent by distillation under reduced pressure. The residuethus obtained was subjected to column chromatography through silica gelusing a 3 : 1 : 0.5 by volume mixture of hexane, ethyl acetate andacetic acid as the eluent, to afford 180 mg of the title compound as apale yellow powder, melting at 197°-199° C.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide,270 MHz), δ ppm: 1.32 (3H, singlet); 1.8-2.1 (2H, multiplet); 1.94 (3H,singlet); 2.08 (6H, singlet); 2.60 (2H, broad triplet, J=6 Hz); 4.07 and4.11 (2H, AB type, J=10 Hz); 4.18 (2H, singlet); 7.14 (2H, doublet, J=9Hz); 7.54 (2H, doublet, J=9 Hz); 7.75 (1H, singlet); 12.50 (1H, broadsinglet).

EXAMPLE 75-{4-[6-(1-Ethoxycarbonyl-1-methylethoxy)-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4-thiazolidinedione(Compound No. 1-53)

Following the procedure described in Example 5, but using 300 mg of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(prepared as described in Example 3) 150 mg of ethyl α-bromoisobutyrate,70 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 5ml of dimethylformamide, 170 mg of the title compound, melting at69°-72° C., were obtained.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm: 1.35 (3H,triplet, J=7 Hz); 1.41 (9H, singlet); 1.85-2.2 (2H, multiplet); 2.02(3H, singlet); 2.06 (3H, singlet); 2.10 (3H, singlet); 2.60 (2H, broadtriplet, J=6 Hz); 3.98 and 4.04 (2H, AB type, J=9 Hz); 4.27 (2H,quartet, J=7 Hz); 7.01 (2H, doublet, J=9 Hz); 7.44 (2H, doublet, J=9Hz); 7.80 (1H singlet); 8.07 (1H, broad singlet).

EXAMPLE 85-{4-[6-(1-Carboxy-1-methylethoxy)-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4,-thiazolidinedione(Compound No. 1-52)

A mixture of 60 mg of5-{4-[6-(1-ethoxycarbonyl-1-methylethoxy)-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4-thiazolidinedione(prepared as described in Example 7), 0.25 ml of a 2N aqueous solutionof sodium hydroxide and 1 ml of methanol was allowed to stand at roomtemperature for 3 days. At the end of this time, the reaction mixturewas acidified with dilute aqueous hydrochloric acid and extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate, andthen the solvent was removed by distillation under reduced pressure, toafford 40 mg of the title compound as a pale yellow powder.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide,270 MHz), δ ppm: 1.29 (6H, singlet); 1.32 (3H, singlet); 1.8-2.1 (2H,multiplet); 1.92 (3H, singlet); 2.04 (6H, singlet); 2.59 (2H, broadtriplet, J=6 Hz); 4.10 (2H, broad singlet); 7.13 (2H, doublet, J=9 Hz);7.53 (2H, doublet, J=9 Hz); 7.75 (1H, singlet); 12.50 (1H, broadsinglet).

PREPARATION 1 6-Benzyloxy-2,5,7,8-tetramethylchroman-2-methylmethanesulfonate

25.54 g of methanesulfonyl chloride were added dropwise, whilstice-cooling, to a solution of 56.57 g of6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanol dissolved in 560 ml ofmethylene chloride, and the resulting mixture was heated under refluxfor 1 hour. At the end of this time, the reaction mixture was washedwith water, and the solvent was removed by distillation under reducedpressure. After the residue had been triturated with methanol, thecrystals thus obtained were collected by filtration to afford 68.43 g ofthe title compound, melting at 90°-96° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz), δ ppm: 1.30 (3H,singlet); 1.70-2.03 (2H, multiplet); 2.10 (3H, singlet); 2.13 (3H,singlet); 2.20 (3H, singlet); 2.43-2.87 (2H, multiplet); 2.97 (3H,singlet); 4.17 (2H, singlet); 4.67 (2H, singlet); 7.10-7.63 (5H,multiplet).

PREPARATION 2 6-Benzyloxy-2-iodomethyl-.2,5,7,8,-tetramethylchroman

224.8 g of sodium iodide were added to a solution of 40.44 g of6-benzyloxy-2,5,7,8-tetramethylchroman-2-methyl methanesulfonate(prepared as described in Preparation 1) dissolved in 600 ml ofdimethylformamide, and the resulting mixture was heated under reflux for4 hours. At the end of this time, the reaction mixture was extractedwith 200 ml of hexane. The extract was washed with water, and thesolvent was removed by distillation under reduced pressure. After theresidue had been triturated with methanol, the crystals thus obtainedwere collected by filtration to afford 29.14 g of the title compound,melting at 95°-98° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz), δ ppm: 1.47 (3H,singlet); 1.80-2.10 (2H, multiplet); 2.13 (6H, singlet); 2.20 (3H,singlet); 2.33-2.80 (2H, multiplet); 3.30 (2H, singlet); 4.67 (2H,singlet); 7.17-7.63 (5H, multiplet).

PREPARATION 36-Benzyloxy-2-[(4-formylphenyl)oxymethyl]-2,5,7,8-tetramethylchroman

A mixture of 1.63 g of sodium hydride (as a 55% w/w dispersion inmineral oil) and 20 ml of dimethylformamide was cooled in an atmosphereof nitrogen; to the cooled solution were then added dropwise a mixtureof 4.58 g of p-hydroxybenzaldehyde and 30 ml of dimethylformamide,whilst ice-cooling. 10.9 g of6-benzyloxy-2-iodomethyl-2,5,7,8-tetramethylchroman (prepared asdescribed in Preparation 2) and 50 ml of dimethylformamide were thenadded to the resulting solution, and the resulting mixture was heatedunder reflux for 5.5 hours. At the end of this time, the reactionmixture was extracted twice, each time with 100 ml of ethyl acetate. Thecombined extracts were washed with water, and the solvent was thenremoved from the extract by distillation under reduced pressure toafford 10.5 g of the title compound as an oil. Nuclear MagneticResonance Spectrum (CDCl₃, 60 MHz), δ ppm: 1.43 (3H, singlet); 1.63-2.27(2H, multiplet); 2.03 (3H, singlet); 2.13 (3H, singlet); 2.20 (3H,singlet); 2.43-2.90 (2H, multiplet); 4.00 (2H, singlet); 4.63 (2H,singlet); 6.97 (2H, doublet, J=9 Hz); 7.10-7.60 (5H, multiplet); 7.77(2H, doublet, J=9 Hz); 9.77 (1H, singlet).

PREPARATION 45-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-methoxy)-benzyl]-2,4-thiazolidinedione

1.5 g of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedione(prepared as described in Example 3) was dissolved in a mixture of 200ml of acetic acid and 3 ml of water and catalytically reduced at 60°-70°C. for 3 hours under a pressure of 4 kg/cm² of hydrogen in the presenceof 1.5 g of 10% w/w palladium-on-charcoal. At the end of this time, 1.3g of the title compound, melting at 184°-186° C., was obtained from thereaction mixture.

Nuclear Magnetic Resonance Spectrum (hexadeuterated acetone, 60 MHz), δppm: 1.39 (3H, singlet); about 2 (2H, multiplet); 2.02 (3H, singlet);2.09 (3H, singlet); 2.13 (3H, singlet); 2.63 (2H, broad triplet, J=6Hz); 3.07 (1H, doublet of doublets, J=15 & 9 Hz); 3.41 (1H, doublet ofdoublets, J=15 & 4.5 Hz); 3.97 (2H, J=9 Hz); 4.70 (1H, doublet ofdoublets, J=15 & 4.5 Hz); 6.90 (2H, doublet, J=9 Hz); 7.21 (2H, doublet,J=9Hz).

PREPARATION 55-[4-(6-Acetoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzyl]2,4-thiazolidinedione

4.3 g of5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-methoxy)benzylidene]-2,4-thiazolidinedionewere dissolved in a mixture of 200 ml of acetic acid and 20 ml of waterand catalytically reduced at 55°-70° C. under a pressure of 3 kg/cm ofhydrogen for 2.5 hours in the presence of 4.3 g of 10% w/wpalladium-on-charcoal. At the end of this time, the catalyst was removedby filtration from the reaction mixture. The solvent was removed fromthe filtrate by distillation under reduced pressure, and the residuethus obtained was mixed with 80 ml of ethyl acetate and 80 ml of water.The pH of the mixture was adjusted to a value of 7 by the addition of a2N aqueous solution of sodium hydroxide. The ethyl acetate layer wasextracted with 80 ml of water to remove impurities. The aqueous layerwas then extracted with 80 ml of ethyl acetate to give the desiredcompound. The operation was repeated twice. The combined extracts werefreed from the solvent by distillation under reduced pressure to afford3.4 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm: 3.03 (1H,doublet of doublets, J=15, 9 Hz); 3.42 (1H, doublet of doublets, J=15,4.5 Hz); 4.45 (1H, doublet of doublets, J=9, 4.5 Hz).

PREPARATION 65-{4-[6-(1-Carboxy-1-methylethoxy)-2,5,7,8-tetramethylchroman-2-methoxy]benzyl}-2,4-thiazolidinedione

Following a procedure similar to that described in Preparation 5, thetitle compound is synthesized by reduction of5-{4-[6-(1-carboxy-1-methylethoxy)-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}-2,4-thiazolidinedione,prepared as described in Example 8.

The benzylthiazolidine compound prepared in Preparation 6 above is aknown compound and is described in Japanese Patent ProvisionalPublication (Tokkai) No. Sho. 62-5980 (Example 79). Thisbenzylthiazolidine compound is an excellent inhibitor of aldosereductase activity. Accordingly, the benzylidenethiazolidine compoundemployed as a starting material in this Preparation is useful as asynthetic intermediate for preparing the correspondingbenzylthiazolidine compound.

BIOLOGICAL ACTIVITY Inhibitory activity on the formation of lipidperoxide

This was investigated by the ferrous sulfate/cysteine method describedby Malvy et al. [Biochem. Biophys. Res. Commun., 95, 734 (1980)]. Thecompound under test at various concentrations, cysteine (500 μM) andferrous sulfate (5 μM) were added to and allowed to react with a ratliver microsomal preparation. The amount of peroxide thus formed wasmeasured according to the thiobarbituric acid (TBA) method and theconcentration of the compound under test required to inhibit theformation of lipid peroxide by 50% (I₅₀ μg/ml) was calculated. Theresults are reported in Table 3, below. The compounds of the inventionare identified by the number of the Example in which their preparationis illustrated.

                  TABLE 3                                                         ______________________________________                                                   Concentration inhibiting 50% of the                                Example No.                                                                              lipid peroxide formation (μg/ml)                                ______________________________________                                        2          0.03-0.1                                                           3          0.03-0.1                                                           ______________________________________                                    

The results shown above demonstrate that the compounds of the presentinvention strongly inhibit the formation of lipid peroxide, even at lowconcentrations.

We claim:
 1. A compound of formula (I) : ##STR13## wherein R¹, R.sup. 2, R⁴ and R⁵ are each methyl; R³ is hydroxy or acetoxy;W is methylene; and n is
 1. 2. The compound of claim 1, wherein R³ is hydroxy.
 3. The compound of claim 1, wherein R³ is acetoxy.
 4. A pharmaceutical composition for the treatment or prophylaxis of diseases and disorders arising from an imbalance in the lipid peroxide level, said composition comprising an effective amount of an active compound of formula(I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in admixture with a pharmaceutically acceptable carrier or diluent.
 5. A method of reducing lipid peroxide levels in an animal by administering to said animal an effective amount of an active compound, wherein said active compound is selected from the group consisting of compounds of formula (I), as claimed in claim 1, and pharmaceutically acceptable salts thereof. 